bims-traimu 2023-11-26 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2023–11–26
nine papers selected by
Yantong Wan, Southern Medical University

Human monocytes exposed to SARS-CoV-2 display features of innate immune memory producing high levels of CXCL10 upon restimulation.
Acid ceramidase regulates innate immune memory.
Impact of Immunity on Coronary Artery Disease: An Updated Pathogenic Interplay and Potential Therapeutic Strategies.
Innate immune cellular therapeutics in transplantation.
Oxylipin transport by lipoprotein particles and its functional implications for cardiometabolic and neurological disorders.
NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.
Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring.
The Role of Ozone as an Nrf2-Keap1-ARE Activator in the Anti-Microbial Activity and Immunity Modulation of Infected Wounds.
Pediatric sepsis survivors are resistant to sepsis-induced long-term immune dysfunction.

J Innate Immun. 2023 Nov 21.

Human monocytes exposed to SARS-CoV-2 display features of innate immune memory producing high levels of CXCL10 upon restimulation.

Jelena Cvetkovic, Ronald H J Jacobi, Alberto Miranda-Bedate, Nhung Pham, Martina Kutmon, James Groot, Martijn D B van de Garde, Elena Pinelli.

Introduction A role for innate immune memory in protection during COVID-19 infection or vaccination has been recently reported. However, no study so far has shown whether SARS-CoV-2 can train innate immune cells. The aim of this study was to investigate whether this virus can induce trained immunity in human monocytes. Methods Monocytes were exposed to inactivated (i)SARS-CoV-2 for 24 hours, followed by a resting period in medium only and a secondary stimulation on day 6 after which, the cytokine/chemokine and transcriptomic profiles were determined. Results Compared to untrained cells, the iSARS-CoV-2-trained monocytes secreted significantly higher levels of IL-6, TNF-α, CXCL10, CXCL9 and CXCL11 upon restimulation. Transcriptome analysis of iSARS-CoV-2 trained monocytes revealed increased expression of several inflammatory genes. As epigenetic and metabolic modifications are hallmarks of trained immunity, we analyzed the expression of genes related to these processes. Findings indicate that indeed SARS-CoV-2-trained monocytes show changes in the expression of genes involved in metabolic pathways including the tricarboxylic acid (TCA) cycle, amino acid metabolism and the expression of several epigenetic regulator genes. Using epigenetic inhibitors that block histone methyl and acetyl transferases, we observed that the capacity of monocytes to be trained by iSARS-CoV-2 was abolished. Conclusion Overall, our findings indicate that iSARS-CoV-2 can induce properties associated with trained immunity in human monocytes. These results contribute to the knowledge required for improving vaccination strategies to prevent infectious diseases.

DOI: https://doi.org/10.1159/000535120
Cell Rep. 2023 Nov 22. pii: S2211-1247(23)01470-5. [Epub ahead of print]42(12): 113458

Acid ceramidase regulates innate immune memory.

Nils Rother, Cansu Yanginlar, Geoffrey Prévot, Inge Jonkman, Maaike Jacobs, Mandy M T van Leent, Julia van Heck, Vasiliki Matzaraki, Anthony Azzun, Judit Morla-Folch, Anna Ranzenigo, William Wang, Roy van der Meel, Zahi A Fayad, Niels P Riksen, Luuk B Hilbrands, Rik G H Lindeboom, Joost H A Martens, Michiel Vermeulen, Leo A B Joosten, Mihai G Netea, Willem J M Mulder, Johan van der Vlag, Abraham J P Teunissen, Raphaël Duivenvoorden.

  Innate immune memory, also called "trained immunity," is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.

Keywords:  CP: Immunology; acid ceramidase; epigenetics; immune memory; innate immunity; lipid metabolism; monocytes; nanobiologics; sphingolipids; trained immunity

DOI:  https://doi.org/10.1016/j.celrep.2023.113458
Life (Basel). 2023 Oct 27. pii: 2128. [Epub ahead of print]13(11):

Impact of Immunity on Coronary Artery Disease: An Updated Pathogenic Interplay and Potential Therapeutic Strategies.

Nicola Laera, Paolo Malerba, Gaetano Vacanti, Simone Nardin, Matteo Pagnesi, Matteo Nardin.

  Coronary artery disease (CAD) is the leading cause of death worldwide. It is a result of the buildup of atherosclerosis within the coronary arteries. The role of the immune system in CAD is complex and multifaceted. The immune system responds to damage or injury to the arterial walls by initiating an inflammatory response. However, this inflammatory response can become chronic and lead to plaque formation. Neutrophiles, macrophages, B lymphocytes, T lymphocytes, and NKT cells play a key role in immunity response, both with proatherogenic and antiatherogenic signaling pathways. Recent findings provide new roles and activities referring to endothelial cells and vascular smooth muscle cells, which help to clarify the intricate signaling crosstalk between the involved actors. Research is ongoing to explore immunomodulatory therapies that target the immune system to reduce inflammation and its contribution to atherosclerosis. This review aims to summarize the pathogenic interplay between immunity and CAD and the potential therapeutic strategies, and explore immunomodulatory therapies that target the immune system to reduce inflammation and its contribution to atherosclerosis.

Keywords:  atherosclerosis; checkpoints inhibitors; coronary artery disease; innate immunity; trained immunity

DOI:  https://doi.org/10.3390/life13112128
Front Transplant. 2023 ;pii: 1067512. [Epub ahead of print]2

Innate immune cellular therapeutics in transplantation.

Leah C Ott, Alex G Cuenca.

  Successful organ transplantation provides an opportunity to extend the lives of patients with end-stage organ failure. Selectively suppressing the donor-specific alloimmune response, however, remains challenging without the continuous use of non-specific immunosuppressive medications, which have multiple adverse effects including elevated risks of infection, chronic kidney injury, cardiovascular disease, and cancer. Efforts to promote allograft tolerance have focused on manipulating the adaptive immune response, but long-term allograft survival rates remain disappointing. In recent years, the innate immune system has become an attractive therapeutic target for the prevention and treatment of transplant organ rejection. Indeed, contemporary studies demonstrate that innate immune cells participate in both the initial alloimmune response and chronic allograft rejection and undergo non-permanent functional reprogramming in a phenomenon termed "trained immunity." Several types of innate immune cells are currently under investigation as potential therapeutics in transplantation, including myeloid-derived suppressor cells, dendritic cells, regulatory macrophages, natural killer cells, and innate lymphoid cells. In this review, we discuss the features and functions of these cell types, with a focus on their role in the alloimmune response. We examine their potential application as therapeutics to prevent or treat allograft rejection, as well as challenges in their clinical translation and future directions for investigation.

Keywords:  MDSCs (myeloid-derived suppressor cells); cellular therapeutics; human monocyte-derived suppressor cells; innate lymphoid cells (ILCs); regulatory dendritic cells; regulatory macrophages; transplantation

DOI:  https://doi.org/10.3389/frtra.2023.1067512
Prog Lipid Res. 2023 Nov 16. pii: S0163-7827(23)00055-3. [Epub ahead of print] 101265

Oxylipin transport by lipoprotein particles and its functional implications for cardiometabolic and neurological disorders.

Nuanyi Liang, Brian A Harsch, Sitong Zhou, Alison Borkowska, Gregory C Shearer, Rima Kaddurah-Daouk, John W Newman, Kamil Borkowski.

  Lipoprotein metabolism is critical to inflammation. While the periphery and central nervous system (CNS) have separate yet connected lipoprotein systems, impaired lipoprotein metabolism is implicated in both cardiometabolic and neurological disorders. Despite the substantial investigation into the composition, structure and function of lipoproteins, the lipoprotein oxylipin profiles, their influence on lipoprotein functions, and their potential biological implications are unclear. Lipoproteins carry most of the circulating oxylipins. Importantly, lipoprotein-mediated oxylipin transport allows for endocrine signaling by these lipid mediators, long considered to have only autocrine and paracrine functions. Alterations in plasma lipoprotein oxylipin composition can directly impact inflammatory responses of lipoprotein metabolizing cells. Similar investigations of CNS lipoprotein oxylipins are non-existent to date. However, as APOE4 is associated with Alzheimer's disease-related microglia dysfunction and oxylipin dysregulation, ApoE4-dependent lipoprotein oxylipin modulation in neurological pathologies is suggested. Such investigations are crucial to bridge knowledge gaps linking oxylipin- and lipoprotein-related disorders in both periphery and CNS. Here, after providing a summary of existent literatures on lipoprotein oxylipin analysis methods, we emphasize the importance of lipoproteins in oxylipin transport and argue that understanding the compartmentalization and distribution of lipoprotein oxylipins may fundamentally alter our consideration of the roles of lipoprotein in cardiometabolic and neurological disorders.

Keywords:  Alzheimer's disease; Apolipoprotein E4 (ApoE4); COVID-19; Cardiometabolic disorders; Immune memory; Inflammation; Lipoproteins; Neurodegenerative disorders; Neurological disorders; Oxylipins; Trained immunity

DOI:  https://doi.org/10.1016/j.plipres.2023.101265
Int Immunopharmacol. 2023 Nov 20. pii: S1567-5769(23)01584-9. [Epub ahead of print]126 111257

NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.

Yingqian Mi, Mengyan Tang, Qiong Wu, Yinan Wang, Qihui Liu, Pei Zhu, Xiaoyang Xue, Yuntong Liu, Xinyu Chai, Yuyang Hou, Dongmei Yan.

  Bacillus Calmette Guerin (BCG) perfusion is widely used as cancer adjuvant therapy, in which macrophages play an important role. Novel macrophage activated associated protein 1 (NMAAP1), upregulated after BCG's activation, was proved to promote macrophage polarization to the M1 type. We found that BCG could stimulate mice BMDM to the M1 type and kill tumor cells. After the deletion of NMAAP1, the tumor volume of mice became larger, and the number of M1 type macrophages in the tumor decreased significantly. When macrophages were induced into the M1 type, aerobic glycolysis, the Warburg effect manifested in the increased uptake of glucose and the conversion of pyruvate to lactic acid. NMAAP1 could bind with IP3R and regulate macrophage polarization to the M1 type. However, the specific mechanism of how NMAAP1 regulates macrophage polarization towards the M1 type and plays an antitumor role must be clarified. NMAAP1 could promote the release of lactic acid and pyruvate, enhance the glycolysis of macrophages, and affect the expression of HIF-1α. After inhibition of glycolysis by 2-DG and lactic acid generation by FX11, the effects of NMAAP1 promoting macrophage polarization to the antitumor M1 type were weakened. Furthermore, NMAAP1 upregulated the expression of HIF-1α, which is associated with glycolysis. Moreover, the Ca2+/NF-κB pathway regulated HIF-1α expression by NMAAP1 in the macrophages. NMAAP1 promotes the polarization of macrophages towards the M1 type by affecting the Warburg effect stimulated by BCG.

Keywords:  BCG; Glycolysis; Macrophages; NMAAP1; Polarization

DOI:  https://doi.org/10.1016/j.intimp.2023.111257
J Clin Invest. 2023 Nov 21. pii: e169730. [Epub ahead of print]

Gestational diabetes in mice induces hematopoietic memory that impacts the long-term health of the offspring.

Vinothini Govindarajah, Masahide Sakabe, Samantha Good, Michael Solomon, Ashok Arasu, Nong Chen, Xuan Zhang, H Leighton Grimes, Ady Kendler, Mei Xin, Damien Reynaud.

  Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the AGER pattern recognition receptor and the NLRP3 inflammasome, which leads to increased placental inflammation. In adult offspring, we find that this memory is associated with DNMT1 upregulation and epigenetic changes in hematopoietic progenitors. Altogether, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes, and that this memory constitutes a new pathway connecting gestational health to adult pathologies.

Keywords:  Cardiovascular disease; Diabetes; Hematology; Hematopoietic stem cells; Inflammation

DOI:  https://doi.org/10.1172/JCI169730
Antioxidants (Basel). 2023 Nov 08. pii: 1985. [Epub ahead of print]12(11):

The Role of Ozone as an Nrf2-Keap1-ARE Activator in the Anti-Microbial Activity and Immunity Modulation of Infected Wounds.

Marianno Franzini, Luigi Valdenassi, Sergio Pandolfi, Umberto Tirelli, Giovanni Ricevuti, Salvatore Chirumbolo.

  Ozone is an allotrope of oxygen, widely known to exert an anti-oxidant potential. The ability of low, controlled and standardized doses of ozone in the ozone adjunct treatment of bacterial infections, which occur in wounds, is engaging clinical research to deepen the role of ozone in eradicating even multidrug-resistant bacteria. Ozone activates the nuclear factor erythroid 2-related factor 2 (Nrf2), and this activation triggers a complex cascade of events, which ultimately leads to macrophage training and an improvement in their ability to operate a clearance of bacteria in the patient's anatomical districts. In this review, we try to elucidate the recent evidence about the mechanisms with which ozone can actually remove bacteria and even multi-drug-resistant (MDR) bacteria, accounting on its complex ability in modulating immunity.

Keywords:  Nrf2; immunity; macrophage; macrophage training; ozone; tolerance

DOI:  https://doi.org/10.3390/antiox12111985
Br J Pharmacol. 2023 Nov 22.

Pediatric sepsis survivors are resistant to sepsis-induced long-term immune dysfunction.

David F Colón, Carlos W Wanderley, Walter M Turato, Vanessa F Borges, Marcelo Franchin, Fernanda V S Castanheira, Daniele Nascimento, Douglas Prado, Mikhael Haruo Fernandes de Lima, Leila C Volpon, Silvia K Kavaguti, Ana P Carlotti, Fabio Carmona, Bernardo S Franklin, Thiago M Cunha, Jose C Alves-Filho, Fernando Q Cunha.

   BACKGROUND AND PURPOSE: Sepsis-surviving adult individuals commonly develop immunosuppression and increased susceptibility to secondary infections, outcome mediated by the axis IL-33/ILC2s/M2 macrophages/Tregs. Nonetheless, the long-term immune consequences of pediatric sepsis are indeterminate. We sought to investigate the role of age in the genesis of immunosuppression following sepsis.
EXPERIMENTAL APPROACH: Here, we compared the frequency of Tregs, the activation of the IL33/ILC2s axis in M2 macrophages, and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. Likewise, sepsis-surviving mice were inoculated intranasally with Pseudomonas aeruginosa or by subcutaneous inoculation of the B16 melanoma cell line. Finally, blood samples from sepsis-surviving patients were collected and the concentrations of IL-33 and Tregs frequency were assessed.
KEY RESULTS: In contrast to 6-week-old, 2-week-old mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in 6-week-old but not 2-week-old post-septic mice. Moreover, impaired IL-33 production in 2-week-old post-septic mice was associated with increased DNA methylation in lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in 2-week-old mice. Clinically, adults but not pediatric post-septic patients exhibited higher counts of Tregs and sera IL-33 levels.
CONCLUSION AND IMPLICATIONS: These findings demonstrate a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression. Thus, a better understanding of this process could lead to differential treatments for adult and pediatric sepsis.

Keywords:  IL-33; M2 macrophages; Tregs; pediatric sepsis; sepsis-induced immunosuppression

DOI:  https://doi.org/10.1111/bph.16286