bims-imicid 2023-10-22 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–10–22
38 papers selected by
Dylan Ryan, University of Cambridge

Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.
Proline uptake promotes activation of lymphoid tissue inducer cells to maintain gut homeostasis.
Global lactylome reveals lactylation-dependent mechanisms underlying TH17 differentiation in experimental autoimmune uveitis.
Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release.
Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing.
Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.
An early glycolysis burst in microglia regulates mitochondrial dysfunction in oligodendrocytes under neuroinflammation.
Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.
ABHD6 suppression promotes anti-inflammatory polarization of adipose tissue macrophages via 2-monoacylglycerol/PPAR signaling in obese mice.
Macrophage immunometabolism in diabetes-associated atherosclerosis.
Metabolic advantages of regulatory T cells dictated by cancer cells.
Electrical stimulation facilitates NADPH production in pentose phosphate pathway and exerts an anti-inflammatory effect in macrophages.
Noninvasive assessment of metabolic turnover during inflammation by in vivo deuterium magnetic resonance spectroscopy.
Novel insights into the role of acetyl-CoA producing enzymes in epigenetic regulation.
Heme oxygenase-1 increases intracellular iron storage and suppresses inflammatory response of macrophages by inhibiting M1 polarization.
Mitochondrial metabolism in Drosophila macrophage-like cells regulates body growth via modulation of cytokine and insulin signaling.
Polyamines and hypusination are important for Clostridioides difficile toxin B (TcdB)-mediated activation of group 3 innate lymphocytes (ILC3s).
Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation.
Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug-Gene Networks: From Biology to Precision Therapeutics.
Mouse Memory CD8 T Cell Subsets Defined by Tissue-Resident Memory Integrin Expression Exhibit Distinct Metabolic Profiles.
Metabolic reprogramming, autophagy, and ferroptosis: Novel arsenals to overcome immunotherapy resistance in gastrointestinal cancer.
Porphyromonas gingivalis outer membrane vesicles shape trophoblast cell metabolism impairing functions associated to adverse pregnancy outcome.
RGS1 Modulates Autophagic and Metabolic Programs and Is a Critical Mediator of Human Regulatory T Cell Function.
Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.
The NLR immune receptor ADR1 and lipase-like proteins EDS1 and PAD4 mediate stomatal immunity in Nicotiana benthamiana and Arabidopsis.
Intestinal microbial circadian rhythms drive sex differences in host immunity and metabolism.
Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases.
Taurine reduction of injury from neutrophil infiltration ameliorates Streptococcus uberis-induced mastitis.
Angiotensin II type 1 receptor-associated protein in immune cells: a possible key factor in the pathogenesis of visceral obesity.
Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.
Besnoitia besnoiti-induced neutrophil clustering and neutrophil extracellular trap formation depend on P2X1 purinergic receptor signaling.
Distinct defects in early innate and late adaptive immune responses typify impaired fracture healing in diet-induced obesity.
Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.
Macrophage polarization and metabolism in atherosclerosis.
A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.
Discrete interplay of gut microbiota L-tryptophan metabolites in host biology and disease.
Obesity dysregulates the pulmonary antiviral immune response.
The alterations of innate immunity and enhanced severity of infections in diabetes mellitus.

Immunity. 2023 Oct 08. pii: S1074-7613(23)00417-X. [Epub ahead of print]

Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.

Chunyuan Zhao, Yunjin Ma, Minghui Zhang, Xiaoyan Gao, Wenbo Liang, Ying Qin, Yue Fu, Mutian Jia, Hui Song, Chengjiang Gao, Wei Zhao.

  Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses. Mechanistically, spermine and spermidine induced the transition of B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity with cGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreases the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1 deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-form conformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.

Keywords:  B-DNA; Z-DNA; cGAS; innate immunity; polyamine metabolism; spermidine; spermine; type I IFNs

DOI:  https://doi.org/10.1016/j.immuni.2023.09.012
Nat Metab. 2023 Oct 19.

Proline uptake promotes activation of lymphoid tissue inducer cells to maintain gut homeostasis.

Di Wu, Zongxian Li, Yime Zhang, Yinlian Zhang, Guanqun Ren, Yanyu Zeng, Huiying Liu, Weiqiang Guan, Xingyu Zhao, Peng Li, Luni Hu, Zhiyuan Hou, Jingjing Gong, Jun Li, Wenfei Jin, Zeping Hu, Changtao Jiang, Houhua Li, Chao Zhong.

Metabolic regulation is integral to the proper functioning of innate lymphoid cells, yet the underlying mechanisms remain elusive. Here, we show that disruption of exogenous proline uptake, either through dietary restriction or by deficiency of the proline transporter Slc6a7, in lymphoid tissue inducer (LTi) cells, impairs LTi activation and aggravates dextran sodium sulfate-induced colitis in mice. With an integrative transcriptomic and metabolomic analysis, we profile the metabolic characteristics of various innate lymphoid cell subsets and reveal a notable enrichment of proline metabolism in LTi cells. Mechanistically, defective proline uptake diminishes the generation of reactive oxygen species, previously known to facilitate LTi activation. Additionally, LTi cells deficient in Slc6a7 display downregulation of Cebpb and Kdm6b, resulting in compromised transcriptional and epigenetic regulation of interleukin-22. Furthermore, our study uncovers the therapeutic potential of proline supplementation in alleviating colitis. Therefore, these findings shed light on the role of proline in facilitating LTi activation and ultimately contributing to gut homeostasis.

DOI: https://doi.org/10.1038/s42255-023-00908-6
Sci Adv. 2023 Oct 20. 9(42): eadh4655

Global lactylome reveals lactylation-dependent mechanisms underlying TH17 differentiation in experimental autoimmune uveitis.

Wei Fan, Xiaotang Wang, Shuhao Zeng, Na Li, Guoqing Wang, Ruonan Li, Siyuan He, Wanqian Li, Jiaxing Huang, Xingran Li, Jiangyi Liu, Shengping Hou.

Dysregulation of CD4+ T cell differentiation is linked to autoimmune diseases. Metabolic reprogramming from oxidative phosphorylation to glycolysis and accumulation of lactate are involved in this process. However, the underlying mechanisms remain unclear. Our study showed that lactate-derived lactylation regulated CD4+ T cell differentiation. Lactylation levels in CD4+ T cells increased with the progression of experimental autoimmune uveitis (EAU). Inhibition of lactylation suppressed TH17 differentiation and attenuated EAU inflammation. The global lactylome revealed the landscape of lactylated sites and proteins in the CD4+ T cells of normal and EAU mice. Specifically, hyperlactylation of Ikzf1 at Lys164 promoted TH17 differentiation by directly modulating the expression of TH17-related genes, including Runx1, Tlr4, interleukin-2 (IL-2), and IL-4. Delactylation of Ikzf1 at Lys164 impaired TH17 differentiation. These findings exemplify how glycolysis regulates the site specificity of protein lactylation to promote TH17 differentiation and implicate Ikzf1 lactylation as a potential therapeutic target for autoimmune diseases.

DOI: https://doi.org/10.1126/sciadv.adh4655
Sci Adv. 2023 Oct 20. 9(42): eadj4198

Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release.

Tomoyuki Shiota, Zhucui Li, Guan-Yuan Chen, Kevin L McKnight, Takayoshi Shirasaki, Bryan Yonish, Heyjeong Kim, Ethan J Fritch, Timothy P Sheahan, Masamichi Muramatsu, Maryna Kapustina, Craig E Cameron, You Li, Qibin Zhang, Stanley M Lemon.

Virus-induced changes in host lipid metabolism are an important but poorly understood aspect of viral pathogenesis. By combining nontargeted lipidomics analyses of infected cells and purified extracellular quasi-enveloped virions with high-throughput RNA sequencing and genetic depletion studies, we show that hepatitis A virus, an hepatotropic picornavirus, broadly manipulates the host cell lipid environment, enhancing synthesis of ceramides and other sphingolipids and transcriptionally activating acyl-coenzyme A synthetases and fatty acid elongases to import and activate long-chain fatty acids for entry into the fatty acid elongation cycle. Phospholipids with very-long-chain acyl tails (>C22) are essential for genome replication, whereas increases in sphingolipids support assembly and release of quasi-enveloped virions wrapped in membranes highly enriched for sphingomyelin and very-long-chain ceramides. Our data provide insight into how a pathogenic virus alters lipid flux in infected hepatocytes and demonstrate a distinction between lipid species required for viral RNA synthesis versus nonlytic quasi-enveloped virus release.

DOI: https://doi.org/10.1126/sciadv.adj4198
Cell Rep. 2023 Oct 13. pii: S2211-1247(23)01276-7. [Epub ahead of print]42(10): 113264

Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing.

Xuan Gu, Kailing Li, Meng Zhang, Yandan Chen, Jingchao Zhou, Chunxu Yao, Yong Zang, Jiefeng He, Jun Wan, Bin Guo.

  Aspartyl-tRNA synthetase 2 (Dars2) is involved in the regulation of mitochondrial protein synthesis and tissue-specific mitochondrial unfolded protein response (UPRmt). The role of Dars2 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) is unknown. Here, we show that knockout (KO) of Dars2 significantly impairs the maintenance of hematopoietic stem and progenitor cells (HSPCs) without involving its tRNA synthetase activity. Dars2 KO results in significantly reduced expression of Srsf2/3/6 and impairs multiple events of mRNA alternative splicing (AS). Dars2 directly localizes to Srsf3-labeled spliceosomes in HSPCs and regulates the stability of Srsf3. Dars2-deficient HSPCs exhibit aberrant AS of mTOR and Slc22a17. Dars2 KO greatly suppresses the levels of labile ferrous iron and iron-sulfur cluster-containing proteins, which dampens mitochondrial metabolic activity and DNA damage repair pathways in HSPCs. Our study reveals that Dars2 plays a crucial role in the iron-sulfur metabolism and maintenance of HSPCs by modulating RNA splicing.

Keywords:  CP: Metabolism; CP: Stem cell research

DOI:  https://doi.org/10.1016/j.celrep.2023.113264
Cell Metab. 2023 Oct 15. pii: S1550-4131(23)00367-4. [Epub ahead of print]

Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses.

Yuerong Zhang, Xiaoyan Yu, Rujuan Bao, Haiyan Huang, Chuanjia Gu, Qianming Lv, Qiaoqiao Han, Xian Du, Xu-Yun Zhao, Youqiong Ye, Ren Zhao, Jiayuan Sun, Qiang Zou.

  Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8+ T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8+ T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8+ T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.

Keywords:  adipocyte metabolism; antitumor CD8(+) T cell responses; dietary fructose; mTORC1

DOI:  https://doi.org/10.1016/j.cmet.2023.09.011
iScience. 2023 Oct 20. 26(10): 107921

An early glycolysis burst in microglia regulates mitochondrial dysfunction in oligodendrocytes under neuroinflammation.

Hamid Suhail, Mohammad Nematullah, Faraz Rashid, Mir Sajad, Mena Fatma, Jaspreet Singh, Insha Zahoor, Wing Lee Cheung, Nivedita Tiwari, Kameshwar Ayasolla, Ashok Kumar, Nasrul Hoda, Ramandeep Rattan, Shailendra Giri.

  Metabolism and energy processes governing oligodendrocyte function during neuroinflammatory disease are of great interest. However, how varied cellular environments affect oligodendrocyte activity during neuroinflammation is unknown. We demonstrate that activated microglial energy metabolism controls oligodendrocyte mitochondrial respiration and activity. Lipopolysaccharide/interferon gamma promote glycolysis and decrease mitochondrial respiration and myelin protein synthesis in rat brain glial cells. Enriched microglia showed an early burst in glycolysis. In microglia-conditioned medium, oligodendrocytes did not respire and expressed less myelin. SCENITH revealed metabolic derangement in microglia and O4-positive oligodendrocytes in endotoxemia and experimental autoimmune encephalitogenic models. The early burst of glycolysis in microglia was mediated by PDPK1 and protein kinase B/AKT signaling. We found that microglia-produced NO and itaconate, a tricarboxylic acid bifurcated metabolite, reduced mitochondrial respiration in oligodendrocytes. During inflammation, we discovered a signaling pathway in microglia that could be used as a therapeutic target to restore mitochondrial function in oligodendrocytes and induce remyelination.

Keywords:  Cellular neuroscience; Immune response; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2023.107921
Curr Opin Biotechnol. 2023 Oct 18. pii: S0958-1669(23)00118-0. [Epub ahead of print]84 103008

Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.

Helena B Madsen, Marlies Jw Peeters, Per Thor Straten, Claus Desler.

Nucleotide metabolism plays a crucial role in the regulation of the tumor microenvironment (TME) and immune cell function. In the TME, limited availability of nucleotide precursors due to increased consumption by tumor cells and T cells affects both tumor development and immune function. Metabolic reprogramming in tumor cells favors pathways supporting growth and proliferation, including nucleotide synthesis. Additionally, extracellular nucleotides, such as ATP and adenosine, exhibit dual roles in modulating immune function and tumor cell survival. ATP stimulates antitumor immunity by activating purinergic receptors, while adenosine acts as a potent immunosuppressor. Targeting nucleotide metabolism in the TME holds immense promise for cancer therapy. Understanding the intricate relationship between nucleotide metabolism, the TME, and immune responses will pave the way for innovative therapeutic interventions.

DOI: https://doi.org/10.1016/j.copbio.2023.103008
Mol Metab. 2023 Oct 12. pii: S2212-8778(23)00156-4. [Epub ahead of print] 101822

ABHD6 suppression promotes anti-inflammatory polarization of adipose tissue macrophages via 2-monoacylglycerol/PPAR signaling in obese mice.

P Poursharifi, C Schmitt, I Chenier, Y H Leung, A K Oppong, Y Bai, L-L Klein, A Al-Mass, R Lussier, M Abu-Farha, J Abubaker, F Al-Mulla, M-L Peyot, S R M Madiraju, M Prentki.

   OBJECTIVE: Pro-inflammatory polarization of adipose tissue macrophages (ATMs) plays a critical role in the pathogenesis of obesity-associated chronic inflammation. However, little is known about the role of lipids in the regulation of ATMs polarity and inflammation in response to metabolic stress. Deletion of α/β-hydrolase domain-containing 6 (ABHD6), a monoacylglycerol (MAG) hydrolase, has been shown to protect against diet-induced obesity and insulin resistance.
METHODS AND RESULTS: Here we investigated the immunometabolic role of macrophage ABHD6 in response to nutrient excess. Whole-body ABHD6 KO mice on high-fat diet showed lower susceptibility to systemic diet-induced inflammation. Moreover, in the setting of overnutrition, stromal vascular cells from gonadal fat of KO vs. control mice contained lower number of M1 macrophages and exhibited enhanced levels of metabolically activated macrophages (MMe) and M2 markers, oxygen consumption, and interleukin-6 (IL-6) release. Likewise, under in vitro nutri-stress condition, pharmacological inhibition of ABHD6 in MMe-polarized macrophages attenuated the expression and release of pro-inflammatory cytokines and M1 markers and induced the upregulation of lipid metabolism genes. ABHD6-inhibited MMe macrophages showed elevated levels of peroxisome proliferator-activated receptors (PPARs) and 2-MAG species. Notably, among different MAG species, only 2-MAG treatment led to increased levels of PPAR target genes in MMe macrophages.
CONCLUSIONS: Collectively, our findings identify ABHD6 as a key component of pro-inflammatory macrophage activation in response to excess nutrition and implicate an endogenous macrophage lipolysis/2-MAG/PPARs cascade, as a lipid signaling and immunometabolic pathway, which favors the anti-inflammatory polarization of ATMs in obesity.

Keywords:  Immunometabolism; Inflammation; Lipid metabolism; Macrophage; Monoacylglycerol; α/β-hydrolase domain-containing 6

DOI:  https://doi.org/10.1016/j.molmet.2023.101822
Immunometabolism (Cobham). 2023 Oct;5(4): e00032

Macrophage immunometabolism in diabetes-associated atherosclerosis.

Bernardo Gindri Dos Santos, Leigh Goedeke.

  Macrophages play fundamental roles in atherosclerotic plaque formation, growth, and regression. These cells are extremely plastic and perform different immune functions depending on the stimuli they receive. Initial in vitro studies have identified specific metabolic pathways that are crucial for the proper function of pro-inflammatory and pro-resolving macrophages. However, the plaque microenvironment, especially in the context of insulin resistance and type 2 diabetes, constantly challenges macrophages with several simultaneous inflammatory and metabolic stimuli, which may explain why atherosclerosis is accelerated in diabetic patients. In this mini review, we discuss how macrophage mitochondrial function and metabolism of carbohydrates, lipids, and amino acids may be affected by this complex plaque microenvironment and how risk factors associated with type 2 diabetes alter the metabolic rewiring of macrophages and disease progression. We also briefly discuss current challenges in assessing macrophage metabolism and identify future tools and possible strategies to alter macrophage metabolism to improve treatment options for diabetes-associated atherosclerosis.

Keywords:  atherosclerosis; diabetes; insulin resistance; macrophage; metabolism

DOI:  https://doi.org/10.1097/IN9.0000000000000032
Int Immunol. 2023 Oct 14. pii: dxad035. [Epub ahead of print]

Metabolic advantages of regulatory T cells dictated by cancer cells.

Masaki Kondo, Shogo Kumagai, Hiroyoshi Nishikawa.

  Cancer cells employ glycolysis for their survival and growth (the 'Warburg effect'). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop 'immune metabolism-based precision medicine'.

Keywords:  metabolism; regulatory T cell

DOI:  https://doi.org/10.1093/intimm/dxad035
Sci Rep. 2023 Oct 19. 13(1): 17819

Electrical stimulation facilitates NADPH production in pentose phosphate pathway and exerts an anti-inflammatory effect in macrophages.

Mikiko Uemura, Noriaki Maeshige, Atomu Yamaguchi, Xiaoqi Ma, Mami Matsuda, Yuya Nishimura, Tomohisa Hasunuma, Taketo Inoue, Jiawei Yan, Ji Wang, Hiroyo Kondo, Hidemi Fujino.

Macrophages play an important role as effector cells in innate immune system. Meanwhile, macrophages activated in a pro-inflammatory direction alter intracellular metabolism and damage intact tissues by increasing reactive oxygen species (ROS). Electrical stimulation (ES), a predominant physical agent to control metabolism in cells and tissues, has been reported to exert anti-inflammatory effect on immune cells. However, the mechanism underlying the anti-inflammatory effects by ES is unknown. This study aimed to investigate the effect of ES on metabolism in glycolytic-tricarboxylic acid cycle (TCA) cycle and inflammatory responses in macrophages. ES was performed on bone marrow-derived macrophages and followed by a stimulation with LPS. The inflammatory cytokine expression levels were analyzed by real-time polymerase chain reaction and ELISA. ROS production was analyzed by CellRox Green Reagent and metabolites by capillary electrophoresis-mass spectrometry. As a result, ES significantly reduced proinflammatory cytokine expression levels and ROS generation compared to the LPS group and increased glucose-1-phosphate, a metabolite of glycogen. ES also increased intermediate metabolites of the pentose phosphate pathway (PPP); ribulose-5-phosphate, rebose-5 phosphate, and nicotinamide adenine dinucleotide phosphate, a key factor of cellular antioxidation systems, as well as α-Ketoglutarate, an anti-oxidative metabolite in the TCA cycle. Our findings imply that ES enhanced NADPH production with enhancement of PPP, and also decreased oxidative stress and inflammatory responses in macrophages.

DOI: https://doi.org/10.1038/s41598-023-44886-x
Front Immunol. 2023 ;14 1258027

Noninvasive assessment of metabolic turnover during inflammation by in vivo deuterium magnetic resonance spectroscopy.

Vera Flocke, Sebastian Temme, Pascal Bouvain, Maria Grandoch, Ulrich Flögel.

   Background: Inflammation and metabolism exhibit a complex interplay, where inflammation influences metabolic pathways, and in turn, metabolism shapes the quality of immune responses. Here, glucose turnover is of special interest, as proinflammatory immune cells mainly utilize glycolysis to meet their energy needs. Noninvasive approaches to monitor both processes would help elucidate this interwoven relationship to identify new therapeutic targets and diagnostic opportunities.
Methods: For induction of defined inflammatory hotspots, LPS-doped Matrigel plugs were implanted into the neck of C57BL/6J mice. Subsequently, 1H/19F magnetic resonance imaging (MRI) was used to track the recruitment of 19F-loaded immune cells to the inflammatory focus and deuterium (2H) magnetic resonance spectroscopy (MRS) was used to monitor the metabolic fate of [6,6-2H2]glucose within the affected tissue. Histology and flow cytometry were used to validate the in vivo data.
Results: After plug implantation and intravenous administration of the 19F-containing contrast agent, 1H/19F MRI confirmed the infiltration of 19F-labeled immune cells into LPS-doped plugs while no 19F signal was observed in PBS-containing control plugs. Identification of the inflammatory focus was followed by i.p. bolus injection of deuterated glucose and continuous 2H MRS. Inflammation-induced alterations in metabolic fluxes could be tracked with an excellent temporal resolution of 2 min up to approximately 60 min after injection and demonstrated a more anaerobic glucose utilization in the initial phase of immune cell recruitment.
Conclusion: 1H/2H/19F MRI/MRS was successfully employed for noninvasive monitoring of metabolic alterations in an inflammatory environment, paving the way for simultaneous in vivo registration of immunometabolic data in basic research and patients.

Keywords:  deuterium; glycolysis; inflammation; magnetic resonance spectroscopy and imaging; metabolism; neutrophils

DOI:  https://doi.org/10.3389/fimmu.2023.1258027
Front Endocrinol (Lausanne). 2023 ;14 1272646

Novel insights into the role of acetyl-CoA producing enzymes in epigenetic regulation.

Marta Russo, Francesco Pileri, Serena Ghisletti.

  Inflammation-dependent changes in gene expression programs in innate immune cells, such as macrophages, involve extensive reprogramming of metabolism. This reprogramming is essential for the production of metabolites required for chromatin modifications, such as acetyl-CoA, and regulate their usage and availability impacting the macrophage epigenome. One of the most transcriptionally induced proinflammatory mediator is nitric oxide (NO), which has been shown to inhibit key metabolic enzymes involved in the production of these metabolites. Recent evidence indicates that NO inhibits mitochondrial enzymes such as pyruvate dehydrogenase (PDH) in macrophages induced by inflammatory stimulus. PDH is involved in the production of acetyl-CoA, which is essential for chromatin modifications in the nucleus, such as histone acetylation. In addition, acetyl-CoA levels in inflamed macrophages are regulated by ATP citrate lyase (ACLY) and citrate transporter SLC25A1. Interestingly, acetyl-CoA producing enzymes, such as PDH and ACLY, have also been reported to be present in the nucleus and to support the local generation of cofactors such as acetyl-CoA. Here, we will discuss the mechanisms involved in the regulation of acetyl-CoA production by metabolic enzymes, their inhibition by prolonged exposure to inflammation stimuli, their involvement in dynamic inflammatory expression changes and how these emerging findings could have significant implications for the design of novel therapeutic approaches.

Keywords:  acetyl-CoA; chromatin; inflammation; macrophages; mitochondrial enzymes; nitric oxide; transcription

DOI:  https://doi.org/10.3389/fendo.2023.1272646
Metallomics. 2023 Oct 14. pii: mfad062. [Epub ahead of print]

Heme oxygenase-1 increases intracellular iron storage and suppresses inflammatory response of macrophages by inhibiting M1 polarization.

Xueyou Tang, Yunqin Li, Jing Zhao, Li Liang, Kang Zhang, Xiaofeng Zhang, Hong Yu, Huahua Du.

  Heme oxygenase-1 (HO-1) catalyzes the first and rate-limiting enzymatic step of heme degradation, producing carbon monoxide, biliverdin and free iron. Most iron is derived from aged erythrocytes by the decomposition of heme, which happened mainly in macrophages. However, the role of HO-1 on iron metabolism and function of macrophage is unclear. The present study investigated the effect of HO-1 on iron metabolism in macrophages, and explored the role of HO-1 on inflammatory response, polarization and migration of macrophages. HO-1 inducer Hemin or HO-1 inhibitor zinc protoporphyrin (ZnPP) was intravenously injected to C57BL/6 J mice every 4 days for 28 days. We found that HO-1 was mainly located in the cytoplasm of splenic macrophages of mice. Activation of HO-1 by Hemin significantly increased iron deposition in the spleen, upregulated the gene expression of ferritin and ferroportin, and downregulated gene expression of divalent metal transporter 1 (DMT1) and hepcidin. Induced HO-1 by Hemin treatment increased intracellular iron levels of macrophages, slowed down the absorption of extracellular iron and accelerated the excretion of intracellular iron. In addition, activation of HO-1 significantly decreased the expression of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β and inducible nitric oxide synthase (iNOS), but increased the expression of anti-inflammatory cytokines such as IL-10. Furthermore, activation of HO-1 inhibited macrophages to M1-type polarization, and increased the migration rate of macrophages. This study demonstrated that HO-1 was able to regulate iron metabolism, exert anti-inflammatory effects, and inhibit macrophages polarization to M1 type.

Keywords:  HO-1; Hemin; inflammatory response; iron metabolism; macrophage polarization; macrophages

DOI:  https://doi.org/10.1093/mtomcs/mfad062
Biol Open. 2023 Oct 13. pii: bio.059968. [Epub ahead of print]

Mitochondrial metabolism in Drosophila macrophage-like cells regulates body growth via modulation of cytokine and insulin signaling.

Shrivani Sriskanthadevan-Pirahas, Abdul Qadeer Tinwala, Michael J Turingan, Shahoon Khan, Savraj S Grewal.

  Macrophages play critical roles in regulating and maintaining tissue and whole-body metabolism in normal and disease states. While the cell-cell signaling pathways that underlie these functions are becoming clear, less is known about how alterations in macrophage metabolism influence their roles as regulators of systemic physiology. Here, we investigate this by examining Drosophila macrophage-like cells called hemocytes. We used knockdown of TFAM, a mitochondrial genome transcription factor, to reduce mitochondrial OxPhos activity specifically in larval hemocytes. We find that this reduction in hemocyte OxPhos leads to a decrease in larval growth and body size. These effects are associated with a suppression of systemic insulin, the main endocrine stimulator of body growth. We also find that TFAM knockdown leads to decreased hemocyte JNK signaling and decreased expression of the TNF alpha homolog, Eiger in hemocytes. Furthermore, we show that genetic knockdown of hemocyte JNK signaling or Eiger expression mimics the effects of TFAM knockdown and leads to a non-autonomous suppression of body size without altering hemocyte numbers. Our data suggest that modulation of hemocyte mitochondrial metabolism can determine their non-autonomous effects on organismal growth by altering cytokine and systemic insulin signaling. Given that nutrient availability can control mitochondrial metabolism, our findings may explain how macrophages function as nutrient-responsive regulators of tissue and whole-body physiology and homeostasis.

Keywords:   Drosophila ; Cytokine TNF-α/Eiger; Hemocytes; Insulin signaling; JNK signaling; Metabolism; Mitochondria; OxPhos; Systemic growth; TFAM

DOI:  https://doi.org/10.1242/bio.059968
Infect Immun. 2023 Oct 20. e0023623

Polyamines and hypusination are important for Clostridioides difficile toxin B (TcdB)-mediated activation of group 3 innate lymphocytes (ILC3s).

Prakash Sah, Bailey A Knighten, Megan A Reidy, Lauren A Zenewicz.

  Clostridioides difficile is the most common cause of nosocomial gastrointestinal tract bacterial infections. We lack fully effective reliable treatments for this pathogen, and there is a critical need to better understand how C. difficile interacts with our immune system. Group 3 innate lymphocytes (ILC3s) are rare immune cells localized within mucosal tissues that protect against bacterial infections. Upon activation, ILC3s secrete high levels of the cytokine interleukin-22 (IL-22), which is a critical regulator of tissue responses during infection. C. difficile toxin B (TcdB), the major virulence factor, directly activates ILC3s, resulting in high IL-22 levels. We previously reported that polyamines are important in the activation of ILC3s by the innate cytokine interleukin-23 (IL-23) but did not identify a specific mechanism. In this study, we examine how a pathogen impacts a metabolic pathway important for immune cell function and hypothesized that polyamines are important in TcdB-mediated ILC3 activation. We show that TcdB upregulates the polyamine biosynthesis pathway, and the inhibition of the pathway decreases TcdB-mediated ILC3 activation. Two polyamines, putrescine and spermidine, are involved. Spermidine is the key polyamine in the hypusination of eukaryotic initiation factor 5A (eIF5A), and the inhibition of eIF5A reduced ILC3 activation. Thus, there is potential to leverage polyamines in ILC3s to promote activation of ILC3s during C. difficile infection and other bacterial infections where ILC3s serve a protective role.

Keywords:  Clostridioides difficile; bacterial toxins; cytokines; innate lymphocytes; polyamines

DOI:  https://doi.org/10.1128/iai.00236-23
J Clin Invest. 2023 Oct 16. pii: e166628. [Epub ahead of print]133(20):

Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation.

Xin Wang, Lina Sun, Biao Yang, Wenhua Li, Cangang Zhang, Xiaofeng Yang, Yae Sun, Xiaonan Shen, Yang Gao, Bomiao Ju, Yafeng Gao, Dan Liu, Jiapeng Song, Xiaoxuan Jia, Yanhong Su, Anjun Jiao, Haiyan Liu, Lianjun Zhang, Lan He, Lei Lei, WanJun Chen, Baojun Zhang.

  Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNA-Seq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance.

Keywords:  Adaptive immunity; Autoimmune diseases; Autoimmunity; Immunology; T cells

DOI:  https://doi.org/10.1172/JCI166628
Circulation. 2023 Oct 18.

Cellular Heterogeneity of Activated Primary Human Macrophages and Associated Drug-Gene Networks: From Biology to Precision Therapeutics.

Julius L Decano, Enrico Maiorino, Joan T Matamalas, Sarvesh Chelvanambi, Bart M Tiemeijer, Yoshihiro Yanagihara, Shin Mukai, Prabhash Kumar Jha, Diego V S Pestana, Edwin D'Souza, Mary Whelan, Rile Ge, Takaharu Asano, Amitabh Sharma, Peter Libby, Sasha A Singh, Elena Aikawa, Masanori Aikawa.

   BACKGROUND: Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and the development of novel immune therapies. We hypothesized that the study of macrophage subpopulations could lead to anti-inflammatory interventions.
METHODS: Primary human macrophages activated by IFNγ (M[IFNγ]) underwent analyses by single-cell RNA sequencing, time-course cell-cluster proteomics, metabolite consumption, immunoassays, and functional tests (phagocytic, efferocytotic, and chemotactic). RNA-sequencing data were analyzed in LINCS (Library of Integrated Network-Based Cellular Signatures) to identify compounds targeting M(IFNγ) subpopulations. The effect of compound BI-2536 was tested in human macrophages in vitro and in a murine model of atherosclerosis.
RESULTS: Single-cell RNA sequencing identified 2 major clusters in M(IFNγ): inflammatory (M[IFNγ]i) and phagocytic (M[IFNγ]p). M(IFNγ)i had elevated expression of inflammatory chemokines and higher amino acid consumption compared with M(IFNγ)p. M(IFNγ)p were more phagocytotic and chemotactic with higher Krebs cycle activity and less glycolysis than M(IFNγ)i. Human carotid atherosclerotic plaques contained 2 such macrophage clusters. Bioinformatic LINCS analysis using our RNA-sequencing data identified BI-2536 as a potential compound to decrease the M(IFNγ)i subpopulation. BI-2536 in vitro decreased inflammatory chemokine expression and secretion in M(IFNγ) by shrinking the M(IFNγ)i subpopulation while expanding the M(IFNγ)p subpopulation. BI-2536 in vivo shifted the phenotype of macrophages, modulated inflammation, and decreased atherosclerosis and calcification.
CONCLUSIONS: We characterized 2 clusters of macrophages in atherosclerosis and combined our cellular data with a cell-signature drug library to identify a novel compound that targets a subset of macrophages in atherosclerosis. Our approach is a precision medicine strategy to identify new drugs that target atherosclerosis and other inflammatory diseases.

Keywords:  atherosclerosis; inflammation; macrophages; multiomics; phagocytosis; systems biology

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.064794
Immunohorizons. 2023 Oct 01. 7(10): 652-669

Mouse Memory CD8 T Cell Subsets Defined by Tissue-Resident Memory Integrin Expression Exhibit Distinct Metabolic Profiles.

Mike Sportiello, Alexis Poindexter, Emma C Reilly, Adam Geber, Kris Lambert Emo, Taylor N Jones, David J Topham.

Tissue-resident memory CD8 T cells (TRM) principally reside in peripheral nonlymphoid tissues, such as lung and skin, and confer protection against a variety of illnesses ranging from infections to cancers. The functions of different memory CD8 T cell subsets have been linked with distinct metabolic pathways and differ from other CD8 T cell subsets. For example, skin-derived memory T cells undergo fatty acid oxidation and oxidative phosphorylation to a greater degree than circulating memory and naive cells. Lung TRMs defined by the cell-surface expression of integrins exist as distinct subsets that differ in gene expression and function. We hypothesize that TRM subsets with different integrin profiles will use unique metabolic programs. To test this, differential expression and pathway analysis were conducted on RNA sequencing datasets from mouse lung TRMs yielding significant differences related to metabolism. Next, metabolic models were constructed, and the predictions were interrogated using functional metabolite uptake assays. The levels of oxidative phosphorylation, mitochondrial mass, and neutral lipids were measured. Furthermore, to investigate the potential relationships to TRM development, T cell differentiation studies were conducted in vitro with varying concentrations of metabolites. These demonstrated that lipid conditions impact T cell survival, and that glucose concentration impacts the expression of canonical TRM marker CD49a, with no effect on central memory-like T cell marker CCR7. In summary, it is demonstrated that mouse resident memory T cell subsets defined by integrin expression in the lung have unique metabolic profiles, and that nutrient abundance can alter differentiation.

DOI: https://doi.org/10.4049/immunohorizons.2300040
Cancer Med. 2023 Oct 20.

Metabolic reprogramming, autophagy, and ferroptosis: Novel arsenals to overcome immunotherapy resistance in gastrointestinal cancer.

Xiangwen Wang, Liwen Zhou, Hongpeng Wang, Wei Chen, Lei Jiang, Guangtao Ming, Jun Wang.

   BACKGROUND: Gastrointestinal cancer poses a serious health threat owing to its high morbidity and mortality. Although immune checkpoint blockade (ICB) therapies have achieved meaningful success in most solid tumors, the improvement in survival in gastrointestinal cancers is modest, owing to sparse immune response and widespread resistance. Metabolic reprogramming, autophagy, and ferroptosis are key regulators of tumor progression.
METHODS: A literature review was conducted to investigate the role of the metabolic reprogramming, autophagy, and ferroptosis in immunotherapy resistance of gastrointestinal cancer.
RESULTS: Metabolic reprogramming, autophagy, and ferroptosis play pivotal roles in regulating the survival, differentiation, and function of immune cells within the tumor microenvironment. These processes redefine the nutrient allocation blueprint between cancer cells and immune cells, facilitating tumor immune evasion, which critically impacts the therapeutic efficacy of immunotherapy for gastrointestinal cancers. Additionally, there exists profound crosstalk among metabolic reprogramming, autophagy, and ferroptosis. These interactions are paramount in anti-tumor immunity, further promoting the formation of an immunosuppressive microenvironment and resistance to immunotherapy.
CONCLUSIONS: Consequently, it is imperative to conduct comprehensive research on the roles of metabolic reprogramming, autophagy, and ferroptosis in the resistance of gastrointestinal tumor immunotherapy. This understanding will illuminate the clinical potential of targeting these pathways and their regulatory mechanisms to overcome immunotherapy resistance in gastrointestinal cancers.

Keywords:  autophagy; ferroptosis; gastrointestinal cancer; immunotherapy resistance; metabolic reprogramming

DOI:  https://doi.org/10.1002/cam4.6623
J Cell Physiol. 2023 Oct 16.

Porphyromonas gingivalis outer membrane vesicles shape trophoblast cell metabolism impairing functions associated to adverse pregnancy outcome.

Brenda Lara, Iñaki Loureiro, Laura Gliosca, Lara Castagnola, Fátima Merech, Lucila Gallino, Guillermina Calo, Matías Sassot, Rosanna Ramhorst, Daiana Vota, Claudia Pérez Leirós, Vanesa Hauk.

  Periodontitis is proposed as a risk factor for preterm delivery, fetal growth restriction, and preeclampsia with severe consequences for maternal and neonatal health, but the biological mechanisms involved are elusive. Porphyromonas gingivalis gain access to the placental bed and impair trophoblast cell function, as assessed in murine and human pregnancy, suggesting a pathogenic role in adverse pregnancy and neonatal outcomes. P. gingivalis releases outer membrane vesicles (P. gingivalis OMV) during growth that spread to distant tissues and are internalized in host cells as described in metabolic, neurological, and vascular systemic diseases. Here we tested the hypothesis that P. gingivalis OMV internalized in trophoblast cells disrupt their metabolism leading to trophoblast and placenta dysfunction and adverse pregnancy outcomes. An in vitro design with human trophoblast cells incubated with P. gingivalis OMV was used together with ex vivo and in vivo approaches in pregnant mice treated with P. gingivalis OMV. P. gingivalis OMV modulated human trophoblast cell metabolism by reducing glycolytic pathways and decreasing total reactive oxygen species with sustained mitochondrial activity. Metabolic changes induced by P. gingivalis OMV did not compromise cell viability; instead, it turned trophoblast cells into a metabolic resting state where central functions such as migration and invasion were reduced. The effects of P. gingivalis OMV on human trophoblast cells were corroborated ex vivo in mouse whole placenta and in vivo in pregnant mice: P. gingivalis OMV reduced glycolytic pathways in the placenta and led to lower placental and fetal weight gain in vivo with reduced placental expression of the glucose transporter GLUT1. The present results point to OMV as a key component of P. gingivalis involved in adverse pregnancy outcomes, and even more, unveil a metabolic cue in the deleterious effect of P. gingivalis OMV on trophoblast cells and mouse pregnancy, providing new clues to understand pathogenic mechanisms in pregnancy complications and other systemic diseases.

Keywords:  adverse pregnancy outcome; bacterial extracellular vesicles; metabolic reprogramming; periodontitis; placentation; trophoblast dysfunction

DOI:  https://doi.org/10.1002/jcp.31138
J Immunol. 2023 Oct 18. pii: ji2200402. [Epub ahead of print]

RGS1 Modulates Autophagic and Metabolic Programs and Is a Critical Mediator of Human Regulatory T Cell Function.

Alyssa L Flynn, Joseph Gans, Javier Escobedo, Cheng Zhu, Ana-Maria Florescu, Srinivas Shankara, Stephen L Madden, Peter S Kim, Lily I Pao.

Regulatory T cells (Tregs) are critical mediators of immune tolerance and play a diametric role in cancer and autoimmunity. Tumor-infiltrating Tregs are often associated with poor prognosis in solid tumors because their enrichment in the tumor microenvironment contributes to immunosuppression. Conversely, dysregulation in the Treg compartment can disrupt self-tolerance, leading to autoimmunity. In the present study, we describe what is, to our knowledge, a novel regulator of Tregs, the GTPase activator regulator of G protein 1 (RGS1), demonstrating that RGS1-deficient human Tregs show downregulation of Treg-associated genes and are less immunosuppressive. These RGS1-deficient Tregs exhibit perturbations to the FOXP3-c-MYC transcriptional axis and downstream metabolic and autophagy programs by shifting their energy demands toward glycolysis and rendering them less autophagic. Taken together, RGS1 may serve as an apical node of Treg function by regulating the FOXP3-c-MYC transcriptional axis, thereby providing a therapeutic rationale for targeting RGS1 for treatment of cancer and autoimmune diseases.

DOI: https://doi.org/10.4049/jimmunol.2200402
Cancer Cell. 2023 Oct 16. pii: S1535-6108(23)00328-8. [Epub ahead of print]

Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.

Lauren E Colbert, Molly B El Alam, Rui Wang, Tatiana Karpinets, David Lo, Erica J Lynn, Timothy A Harris, Jacob H Elnaggar, Kyoko Yoshida-Court, Katarina Tomasic, Julianna K Bronk, Julie Sammouri, Ananta V Yanamandra, Adilene V Olvera, Lily G Carlin, Travis Sims, Andrea Y Delgado Medrano, Tatiana Cisneros Napravnik, Madison O'Hara, Daniel Lin, Chike O Abana, Hannah X Li, Patricia J Eifel, Anuja Jhingran, Melissa Joyner, Lilie Lin, Lois M Ramondetta, Andrew M Futreal, Kathleen M Schmeler, Geena Mathew, Stephanie Dorta-Estremera, Jianhua Zhang, Xiaogang Wu, Nadim J Ajami, Matthew Wong, Cullen Taniguchi, Joseph F Petrosino, K Jagannadha Sastry, Pablo C Okhuysen, Sara A Martinez, Lin Tan, Iqbal Mahmud, Philip L Lorenzi, Jennifer A Wargo, Ann H Klopp.

  Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.

Keywords:  cervical cancer; chemoradiation; lactate; metabolism; microbiome; radiation

DOI:  https://doi.org/10.1016/j.ccell.2023.09.012
Plant Cell. 2023 Oct 18. pii: koad270. [Epub ahead of print]

The NLR immune receptor ADR1 and lipase-like proteins EDS1 and PAD4 mediate stomatal immunity in Nicotiana benthamiana and Arabidopsis.

Hanling Wang, Susheng Song, Shang Gao, Qiangsheng Yu, Haibo Zhang, Xiulin Cui, Jun Fan, Xiufang Xin, Yule Liu, Brian Staskawicz, Tiancong Qi.

  In the presence of pathogenic bacteria, plants close their stomata to prevent pathogen entry. Intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogenic effectors and activate effector-triggered immune responses. However, the regulatory and molecular mechanisms of stomatal immunity involving NLR immune receptors are unknown. Here, we show that the Nicotiana benthamiana RPW8-NLR central immune receptor ACTIVATED DISEASE RESISTANCE 1 (NbADR1), together with the key immune proteins ENHANCED DISEASE SUSCEPTIBILITY 1 (NbEDS1) and PHYTOALEXIN DEFICIENT 4 (NbPAD4), plays an essential role in bacterial pathogen- and flg22-induced stomatal immunity by regulating the expression of salicylic acid (SA) and abscisic acid (ABA) biosynthesis or response-related genes. NbADR1 recruits NbEDS1 and NbPAD4 in stomata to form a stomatal immune response complex. The transcription factor NbWRKY40e, in association with NbEDS1 and NbPAD4, modulates the expression of SA and ABA biosynthesis or response-related genes to influence stomatal immunity. NbADR1, NbEDS1, and NbPAD4 are required for the pathogen infection-enhanced binding of NbWRKY40e to the ISOCHORISMATE SYNTHASE 1 promoter. Moreover, the ADR1-EDS1-PAD4 module regulates stomatal immunity in Arabidopsis (Arabidopsis thaliana). Collectively, our findings show the pivotal role of the core intracellular immune receptor module ADR1-EDS1-PAD4 in stomatal immunity, which enables plants to limit pathogen entry.

Keywords:  ADR1-EDS1-PAD4; RNL immune receptors; Stomatal immunity; WRKY40e

DOI:  https://doi.org/10.1093/plcell/koad270
iScience. 2023 Oct 20. 26(10): 107999

Intestinal microbial circadian rhythms drive sex differences in host immunity and metabolism.

Sarah K Munyoki, Julie P Goff, Antonija Kolobaric, Armari Long, Steven J Mullett, Jennifer K Burns, Aaron K Jenkins, Lauren DePoy, Stacy G Wendell, Colleen A McClung, Kathleen E Morrison, Eldin Jašarević.

  Circadian rhythms dynamically regulate sex differences in metabolism and immunity, and circadian disruption increases the risk of metabolic disorders. We investigated the role of sex-specific intestinal microbial circadian rhythms in host metabolism using germ-free and conventionalized mice and manipulation of dietary-derived fat, fiber, and microbiota-accessible carbohydrates. Our findings demonstrate that sex differences in circadian rhythms of genes involved in immunity and metabolism depend on oscillations in microbiota, microbial metabolic functions, and microbial metabolites. Further, we show that consuming an obesogenic, high-fat, low-fiber diet produced sex-specific changes in circadian rhythms in microbiota, metabolites, and host gene expression, which were linked to sex differences in the severity of metabolic dysfunction. Our results reveal that microbial circadian rhythms contribute to sex differences in immunity and metabolism and that dietary factors can entrain new circadian rhythms and modify the magnitude of sex differences in host-microbe circadian dynamics.

Keywords:  Human metabolism; Microbiology; Microbiome

DOI:  https://doi.org/10.1016/j.isci.2023.107999
Mol Biol Rep. 2023 Oct 18.

Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases.

Mohammad Sheibani, Maryam Shayan, Mina Khalilzadeh, Zahra Ebrahim Soltani, Majid Jafari-Sabet, Mehdi Ghasemi, Ahmad Reza Dehpour.

  Tryptophan metabolism along the kynurenine pathway is of central importance for the immune function. It prevents hyperinflammation and induces long-term immune tolerance. Accumulating evidence also demonstrates cytoprotective and immunomodulatory properties of kynurenine pathway in conditions affecting either central or peripheral nervous system as well as other conditions such as inflammatory bowel disease (IBD). Although multilevel association exists between the inflammatory bowel disease (IBD) and various neurologic (e.g., neurodegenerative) disorders, it is believed that the kynurenine pathway plays a pivotal role in the development of both IBD and neurodegenerative disorders. In this setting, there is strong evidence linking the gut-brain axis with intestinal dysfunctions including IBD which is consistent with the fact that the risk of neurodegenerative diseases is higher in IBD patients. This review aims to highlight the role of kynurenine metabolic pathway in various neurologic and psychiatric diseases as well as relationship between IBD and neurodegenerative disorders in the light of the kynurenine metabolic pathway.

Keywords:  Inflammatory bowel disease; Kynurenine pathway; Neurodegenrative diseases; Neurology; Psychiatry; Tryptophan

DOI:  https://doi.org/10.1007/s11033-023-08859-7
Int Immunopharmacol. 2023 Oct 17. pii: S1567-5769(23)01353-X. [Epub ahead of print]124(Pt B): 111028

Taurine reduction of injury from neutrophil infiltration ameliorates Streptococcus uberis-induced mastitis.

Ming Li, Zhenglei Wang, Shaodong Fu, Naiyan Sun, Weizhen Li, Yuanyuan Xu, Xiangan Han, Jinqiu Zhang, Jinfeng Miao.

  Mastitis is a common disease of dairy cows characterized by infiltration of leukocytes, especially neutrophils, resulting in increased permeability of the blood-milk barrier (BMB). Taurine, a functional nutrient, has been shown to have anti-inflammatory and antioxidant effects. Here, we investigated the regulatory effects and mechanisms of taurine on the complex immune network of the mammary gland in Streptococcus uberis (S. uberis) infection. We found that taurine had no direct effect on CXCL2-mediated neutrophil chemotaxis. However, it inhibited MAPK and NF-κB signalings by modulating the activity of TAK1 downstream of TLR2, thereby reducing CXCL2 expression in macrophages to reduce neutrophil recruitment in S. uberis infection. Further, the AMPK/Nrf2 signaling pathway was activated by taurine to help mitigate oxidative damage, apoptosis and disruption of tight junctions in mammary epithelial cells caused by hypochlorous acid, a strong oxidant produced by neutrophils, thus protecting the integrity of the mammary epithelial barrier. Taurine protects the BMB from damage caused by neutrophils via blocking the macrophage-CXCL2-neutrophil signaling axis and increasing the antioxidant capacity of mammary epithelial cells.

Keywords:  AMPK/Nrf2; Blood-milk barrier; Mastitis; Streptococcus uberis; TAK1/MAPK/NF-κB; Taurine

DOI:  https://doi.org/10.1016/j.intimp.2023.111028
Metabolism. 2023 Oct 13. pii: S0026-0495(23)00310-4. [Epub ahead of print]149 155706

Angiotensin II type 1 receptor-associated protein in immune cells: a possible key factor in the pathogenesis of visceral obesity.

Shunichiro Tsukamoto, Toru Suzuki, Hiromichi Wakui, Tatsuki Uehara, Juri Ichikawa, Hiroshi Okuda, Kotaro Haruhara, Kengo Azushima, Eriko Abe, Shohei Tanaka, Shinya Taguchi, Keigo Hirota, Sho Kinguchi, Akio Yamashita, Tomohiko Tamura, Kouichi Tamura.

   BACKGROUND AND AIM: Dysregulation of angiotensin II type 1 receptor-associated protein (ATRAP) expression in cardiovascular, kidney, and adipose tissues is involved in the pathology of hypertension, cardiac hypertrophy, atherosclerosis, kidney injury, and metabolic disorders. Furthermore, ATRAP is highly expressed in bone marrow-derived immune cells; however, the functional role of immune cell ATRAP in obesity-related pathology remains unclear. Thus, we sought to identify the pathophysiological significance of immune cell ATRAP in the development of visceral obesity and obesity-related metabolic disorders using a mouse model of diet-induced obesity.
METHODS: Initially, we examined the effect of high-fat diet (HFD)-induced obesity on the expression of immune cell ATRAP in wild-type mice. Subsequently, we conducted bone marrow transplantation to generate two types of chimeric mice: bone marrow wild-type chimeric (BM-WT) and bone marrow ATRAP knockout chimeric (BM-KO) mice. These chimeric mice were provided an HFD to induce visceral obesity, and then the effects of immune cell ATRAP deficiency on physiological parameters and adipose tissue in the chimeric mice were investigated.
RESULTS: In wild-type mice, body weight increase by HFD was associated with increased expression of immune cell ATRAP. In the bone marrow transplantation experiments, BM-KO mice exhibited amelioration of HFD-induced weight gain and visceral fat expansion with small adipocytes compared BM-WT mice. In addition, BM-KO mice on the HFD showed significant improvements in white adipose tissue metabolism, inflammation, glucose tolerance, and insulin resistance, compared with BM-WT mice on the HFD. Detailed analysis of white adipose tissue revealed significant suppression of HFD-induced activation of transforming growth factor-beta signaling, a key contributor to visceral obesity, via amelioration of CD206+ macrophage accumulation in the adipose tissue of BM-KO mice. This finding suggests a relevant mechanism for the anti-obesity phenotype in BM-KO mice on the HFD. Finally, transcriptome analysis of monocytes indicated the possibility of genetic changes, such as the enhancement of interferon-γ response at the monocyte level, affecting macrophage differentiation in BM-KO mice.
CONCLUSION: Collectively, our results indicate that ATRAP in bone marrow-derived immune cells plays a role in the pathogenesis of visceral obesity. The regulation of ATRAP expression in immune cells may be a key factor against visceral adipose obesity with metabolic disorders.

Keywords:  Adipose tissue; Immune cell; Macrophage; Metabolic disorders; Receptor signaling; Visceral obesity

DOI:  https://doi.org/10.1016/j.metabol.2023.155706
Nat Commun. 2023 Oct 20. 14(1): 6627

Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.

Xudong Chen, Min Xie, Sensen Zhang, Marta Monguió-Tortajada, Jian Yin, Chang Liu, Youqi Zhang, Maeva Delacrétaz, Mingyue Song, Yixue Wang, Lin Dong, Qiang Ding, Boda Zhou, Xiaolin Tian, Haiteng Deng, Lina Xu, Xiaohui Liu, Zi Yang, Qing Chang, Jie Na, Wenwen Zeng, Giulio Superti-Furga, Manuele Rebsamen, Maojun Yang.

Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.

DOI: https://doi.org/10.1038/s41467-023-42210-9
Front Immunol. 2023 ;14 1244068

Besnoitia besnoiti-induced neutrophil clustering and neutrophil extracellular trap formation depend on P2X1 purinergic receptor signaling.

Gabriel Espinosa, Iván Conejeros, Lisbeth Rojas-Barón, Carlos Rodrigo Hermosilla, Anja Taubert.

  Bovine besnoitiosis is a re-emerging cattle disease caused by the cyst-forming apicomplexan parasite Besnoitia besnoiti. Neutrophil extracellular trap (NET) formation represents an efficient innate immune mechanism of polymorphonuclear neutrophils (PMN) against apicomplexan parasites, including B. besnoiti. PMN purinergic signaling was proposed as a critical factor for NET formation. One important purinergic ligand is ATP, which is recognized as a danger signal and released into the extracellular space acting as an autocrine/paracrine signaling molecule. ATP-driven effects on PMN via the nucleotide P2 receptor family include chemotaxis, reactive oxygen species (ROS) production, and NET formation. So far, data on both PMN ATP concentrations and the role of ATP as a key modulator of purinergic signaling in B. besnoiti tachyzoite-triggered bovine NETosis is scarce. Current data showed that B. besnoiti tachyzoite exposure to bovine PMN neither changed total PMN ATP nor extracellular ATP quantities even though it significantly triggered NET formation. Moreover, B. besnoiti tachyzoite-exposed PMN revealed enhanced oxygen consumption rates (OCR) as quantified by the Seahorse metabolic analyzer. Exogenous supplementation of ATP or non-hydrolizable ATP (ATPγS) led to increased extracellular acidification rates (ECAR) but failed to alter tachyzoite-induced oxidative responses (OCR) in exposed PMN. In addition, exogenous supplementation of ATPγS, but not of ATP, boosted B. besnoiti tachyzoite-induced anchored NET formation. Referring to purinergic signaling, B. besnoiti tachyzoite-triggered anchored NET formation revealed P2X1 purinergic as receptor-dependent since it was blocked by the P2X1 inhibitor NF449 at an IC50 of 1.27 µM. In contrast, antagonists of P2Y2, P2Y6, P2X4, and P2X7 purinergic receptors all failed to affect parasite-driven NETosis. As an interesting finding, we additionally observed that B. besnoiti tachyzoite exposure induced PMN clustering in a P2X1-dependent manner. Thus, we identified P2X1 purinergic receptor as a pivotal molecule for both B. besnoiti tachyzoite-induced PMN clustering and anchored NET formation.

Keywords:  ATP; Besnoitia besnoiti; NET formation; PMN; immunometabolism; purinergic receptors

DOI:  https://doi.org/10.3389/fimmu.2023.1244068
Front Immunol. 2023 ;14 1250309

Distinct defects in early innate and late adaptive immune responses typify impaired fracture healing in diet-induced obesity.

Deepak Kumar Khajuria, Irene Reider, Fadia Kamal, Christopher C Norbury, Reyad A Elbarbary.

  Bone fractures, the most common musculoskeletal injuries, heal through three main phases: inflammatory, repair, and remodeling. Around 10% of fracture patients suffer from impaired healing that requires surgical intervention, a huge burden on the healthcare system. The rate of impaired healing increases with metabolic diseases such as obesity-associated hyperglycemia/type 2 diabetes (T2D), an increasing concern given the growing incidence of obesity/T2D. Immune cells play pivotal roles in fracture healing, and obesity/T2D is associated with defective immune-cell functions. However, there is a gap in knowledge regarding the stoichiometry of immune cells that populate the callus and how that population changes during different phases of healing. Here, we used complementary global and single-cell techniques to characterize the repertoire of immune cells in the fracture callus and to identify populations specifically enriched in the fracture callus relative to the unfractured bone or bone marrow. Our analyses identified two clear waves of immune-cell infiltration into the callus: the first wave occurs during the early inflammatory phase of fracture healing, while the second takes place during the late repair/early remodeling phase, which is consistent with previous publications. Comprehensive analysis of each wave revealed that innate immune cells were activated during the early inflammatory phase, but in later phases they returned to homeostatic numbers and activation levels. Of the innate immune cells, distinct subsets of activated dendritic cells were particularly enriched in the inflammatory healing hematoma. In contrast to innate cells, lymphocytes, including B and T cells, were enriched and activated in the callus primarily during the late repair phase. The Diet-Induced Obesity (DIO) mouse, an established model of obesity-associated hyperglycemia and insulin resistance, suffers from multiple healing defects. Our data demonstrate that DIO mice exhibit dysregulated innate immune responses during the inflammatory phase, and defects in all lymphocyte compartments during the late repair phase. Taken together, our data characterize, for the first time, immune populations that are enriched/activated in the callus during two distinct phases of fracture healing and identify defects in the healing-associated immune response in DIO mice, which will facilitate future development of immunomodulatory therapeutics for impaired fracture healing.

Keywords:  adaptive; bone; diabetes; fracture; healing; immunity; innate; obesity

DOI:  https://doi.org/10.3389/fimmu.2023.1250309
Res Sq. 2023 Sep 26. pii: rs.3.rs-3385749. [Epub ahead of print]

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Corina Amor, Inés Fernández-Maestre, Saria Chowdhury, Yu-Jui Ho, Sandeep Nadella, Courtenay Graham, Sebastian E Carrasco, Emmanuella Nnuji-John, Judith Feucht, Clemens Hinterleitner, Valentin J A Barthet, Jacob A Boyer, Riccardo Mezzadra, Matthew G Wereski, David A Tuveson, Ross L Levine, Lee W Jones, Michel Sadelain, Scott W Lowe.

Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline 1,2 . In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness 3-7 . While small-molecule drugs capable of eliminating senescent cells (known as 'senolytics') partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective. As an alternative approach, we have developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and previously showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis 8 . We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, a single administration of a low dose of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

DOI: https://doi.org/10.21203/rs.3.rs-3385749/v1
Cell Death Dis. 2023 Oct 20. 14(10): 691

Macrophage polarization and metabolism in atherosclerosis.

Pengbo Hou, Jiankai Fang, Zhanhong Liu, Yufang Shi, Massimiliano Agostini, Francesca Bernassola, Pierluigi Bove, Eleonora Candi, Valentina Rovella, Giuseppe Sica, Qiang Sun, Ying Wang, Manuel Scimeca, Massimo Federici, Alessandro Mauriello, Gerry Melino.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.

DOI: https://doi.org/10.1038/s41419-023-06206-z
Nat Commun. 2023 Oct 20. 14(1): 6626

A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.

Andras Boeszoermenyi, Léa Bernaleau, Xudong Chen, Felix Kartnig, Min Xie, Haobo Zhang, Sensen Zhang, Maeva Delacrétaz, Anna Koren, Ann-Katrin Hopp, Vojtech Dvorak, Stefan Kubicek, Daniel Aletaha, Maojun Yang, Manuele Rebsamen, Leonhard X Heinz, Giulio Superti-Furga.

Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module. A high-resolution cryo-EM structure of feeblin with SLC15A4 reveals that the inhibitor binds a lysosomal outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to degradation of TASL. This mechanism of action exploits a conformational switch and converts a target-binding event into proteostatic regulation of the effector protein TASL, interrupting the TLR7/8-IRF5 signaling pathway and preventing downstream proinflammatory responses. Considering that all components involved have been genetically associated with systemic lupus erythematosus and that feeblin blocks responses in disease-relevant human immune cells from patients, the study represents a proof-of-concept for the development of therapeutics against this disease.

DOI: https://doi.org/10.1038/s41467-023-42070-3
Mol Cell Biochem. 2023 Oct 20.

Discrete interplay of gut microbiota L-tryptophan metabolites in host biology and disease.

Harmit S Ranhotra.

  The gut microbiota and the host maintain a conjoint relationship and together achieve optimal physiology via a multitude of interactive signalling cues. Dietary-derived L-tryptophan (L-trp) is enzymatically metabolized by the resident symbiotic gut microbiota to indole and various indole derivatives. Indole and indole metabolites secreted by the gut bacteria act locally in the intestinal cells as well as distally and modulate tissue-specific functions which are beneficial to the host. Functions attributed to these microbial indole metabolites in the host include regulation of intestinal permeability, immunity and mucosal roles, inflammation, and insulin sensitivity. On the other hand, dysregulation of gut microbiota L-trp metabolism compromises the optimal availability of indole and indole metabolites and can induce the onset of metabolic disorders, inflammation, liver steatosis, and decrease gut barrier integrity. Gut dysbiosis is regarded as one of the prime reasons for this deregulated microbial-derived indole metabolites. A number of indole metabolites from the gut bacteria have been identified recently displaying variable affinity towards xenobiotic nuclear receptors. Microbial metabolite mimicry concept can be used to design and develop novel indole-moiety-containing compounds with higher affinity towards the receptors and efficacy in preclinical studies. Such compounds may serve as therapeutic drugs in clinical trials in the future. In this article, I review L-trp metabolism in the host and gut microbiota and the various physiological functions, patho-physiologies associated with the microbial-released indole metabolites in the host, including the metabolite mimicry-based concept to develop tailored indole-containing novel experimental drugs.

Keywords:  Gut microbiota; Gut permeability; Host; Indole; Inflammation; L-tryptophan

DOI:  https://doi.org/10.1007/s11010-023-04867-0
Nat Commun. 2023 Oct 19. 14(1): 6607

Obesity dysregulates the pulmonary antiviral immune response.

Mark Almond, Hugo A Farne, Millie M Jackson, Akhilesh Jha, Orestis Katsoulis, Oliver Pitts, Tanushree Tunstall, Eteri Regis, Jake Dunning, Adam J Byrne, Patrick Mallia, Onn Min Kon, Ken A Saunders, Karen D Simpson, Robert J Snelgrove, Peter J M Openshaw, Michael R Edwards, Wendy S Barclay, Liam M Heaney, Sebastian L Johnston, Aran Singanayagam.

Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.

DOI: https://doi.org/10.1038/s41467-023-42432-x
Immunology. 2023 Oct 17.

The alterations of innate immunity and enhanced severity of infections in diabetes mellitus.

Zi Zhou, Hao Wang, Sipin Tan, Huali Zhang, Yaxi Zhu.

  Diabetes mellitus (DM) is a metabolic inflammatory disease with a high incidence worldwide. Patients with DM are at a high risk for all types of infections. Type 1 DM is characterised with immune destruction of pancreatic β cells, while type 2 diabetes is characterised with insulin resistance and β cell dysfunction, both of which result in disorders of glucose and lipid metabolism. This metabolic disorder causes functional defects of immune cells, aberrant production of inflammatory cytokines, dysregulated immune responses, advanced pathophysiological injury of the body, and increased mortality in populations with DM upon infections. Starting with the change of natural immune system in patients with DM, this paper focused on the enhanced severity of infections in DM and the underlying innate immune alterations in preclinical and clinical studies, aiming to better understand the influence of DM on the susceptibility, pathophysiology, and clinical outcomes in infections.

Keywords:  cytokines; diabetes mellitus; infection; innate immunity; macrophages

DOI:  https://doi.org/10.1111/imm.13706