bims-mameti Biomed News
on Macrophage metabolism in inflammation
Issue of 2020‒12‒27
twelve papers selected by
Alessio Menga
University of Turin


  1. EMBO Mol Med. 2020 Dec 22. e12889
    Delaney C, Farrell M, Doherty CP, Brennan K, O'Keeffe E, Greene C, Byrne K, Kelly E, Birmingham N, Hickey P, Cronin S, Savvides SN, Doyle SL, Campbell M.
      Cerebrovascular pathologies occur in up to 80% of cases of Alzheimer's disease; however, the underlying mechanisms that lead to perivascular pathology and accompanying blood-brain barrier (BBB) disruption are still not fully understood. We have identified previously unreported mutations in colony stimulating factor-1 receptor (CSF-1R) in an ultra-rare autosomal dominant condition termed adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP). Cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) and perivascular p-Tau were some of the primary neuropathological features of this condition. We have identified two families with different dominant acting alleles with variants located in the kinase region of the CSF-1R gene, which confer a lack of kinase activity and signalling. The protein product of this gene acts as the receptor for 2 cognate ligands, namely colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). Here, we show that depletion in CSF-1R signalling induces BBB disruption and decreases the phagocytic capacity of peripheral macrophages but not microglia. CSF-1R signalling appears to be critical for macrophage and microglial activation, and macrophage localisation to amyloid appears reduced following the induction of Csf-1r heterozygosity in macrophages. Finally, we show that endothelial/microglial crosstalk and concomitant attenuation of CSF-1R signalling causes re-modelling of BBB-associated tight junctions and suggest that regulating BBB integrity and systemic macrophage recruitment to the brain may be therapeutically relevant in ALSP and other Alzheimer's-like dementias.
    Keywords:  CSF-1; CSF-1R; IL-34; adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP); blood; brain barrier
    DOI:  https://doi.org/10.15252/emmm.202012889
  2. Cancer Lett. 2020 Dec 18. pii: S0304-3835(20)30681-9. [Epub ahead of print]
    Hayes C, Donohoe C, Davern M, Donlon NE.
      The tumour microenvironment is of critical importance in cancer development and progression and includes the surrounding stromal and immune cells, extracellular matrix, and the milieu of metabolites and signalling molecules in the intercellular space. To support sustained mitotic activity cancer cells must reconfigure their metabolic phenotype. Lactate is the major by-product of such metabolic alterations and consequently, accumulates in the tumour. Lactate actively contributes to immune evasion, a hallmark of cancer, by directly inhibiting immune cell cytotoxicity and proliferation. Furthermore, lactate can recruit and induce immunosuppressive cell types, such as regulatory T cells, tumour-associated macrophages, and myeloid-derived suppressor cells which further suppress anti-tumour immune responses. Given its roles in oncogenesis, measuring intratumoural and systemic lactate levels has shown promise as a both predictive and prognostic biomarker in several cancer types. The efficacies of many anti-cancer therapies are limited by an immunosuppressive TME in which lactate is a major contributor, therefore, targeting lactate metabolism is a priority. Developing inhibitors of key proteins in lactate metabolism such as GLUT1, hexokinase, LDH, MCT and HIF have shown promise in preclinical studies, however there is a corresponding lack of success in human trials so far. This may be explained by a weakness of preclinical models that fail to reproduce the complexities of metabolic interactions in natura. The future of these therapies may be as an adjunct to more conventional treatments.
    Keywords:  Immune evasion; Metabolic reprogramming; Oncometabolite; Predictive and prognostic biomarker; Warburg effect
    DOI:  https://doi.org/10.1016/j.canlet.2020.12.021
  3. Exp Cell Res. 2020 Dec 16. pii: S0014-4827(20)30696-0. [Epub ahead of print] 112443
    Zhang J, Zhao WS, Xu L, Wang X, Li XL, Yang XC.
      The hallmark of atherogenesis is characterized as endothelial dysfunction and subsequent macrophage activation. Although our previous study has demonstrated that endothelin-1 (ET-1) plays an important role in atherogenesis, the underlying mechanism remains deeply investigation. Enhanced atherosclerotic plaques were observed in endothelium-specific ET-1 overexpression ApoE-/- mice (eET-1/ApoE-/-) concomitant with increased secretion of pro-inflammatory adhesion molecules and cytokines. The conditional media used for culturing human umbilical vein endothelial cells (HUVECs) with AdET-1 infection and subjected to OX-LDL stimulation, was collected and utilized for bone marrow-derived macrophages (BMDMs) culturing. RT-PCR analysis showed increased genes expression related to classical M1 macrophages but decreased alternative activated M2 macrophages genes expression in macrophage culturing with the conditional media. Furthermore, consistent regulations of macrophage polarization were observed using isolated exosomes from the conditional media. More importantly, we noticed that miR-33 was enriched in the exosomes derived by HUVECs with AdET-1 infection, while bioinformatics analysis further indicated that miR-33 directly targeted NR4A and miR-33/NR4A axis was required for the effect of endothelial-specific ET-1 overexpression on pro-inflammatory macrophage activation. By contrast, such effects could be reversed by ET-1 knockdown. Taken together, our study indicated that the exosomes derived by HUVECs with AdET-1 infection can transfer miR-33 to macrophages and subsequently promote pro-inflammatory macrophage activation by directly targeting to NR4A. These evidences clearly revealed that miR-33/NR4A axis was the important mechanism underlying the effect of ET-1 on macrophage activation and indicated that ET-1 may act as a promising target for atherosclerosis management.
    Keywords:  Endothelial-1; HUVECs; Macrophages; NR4A; miR-33
    DOI:  https://doi.org/10.1016/j.yexcr.2020.112443
  4. Oncoimmunology. 2020 Dec 06. 9(1): 1846915
    de Azevedo RA, Shoshan E, Whang S, Markel G, Jaiswal AR, Liu A, Curran MA, Travassos LR, Bar-Eli M.
      Immune checkpoint blockade (ICB) has demonstrated an impressive outcome in patients with metastatic melanoma, yet, durable complete response; even with Ipilimumab/Nivolumab combo are under 30%. Primary and acquired resistance in response to ICB is commonly due to a tumor immune escape mechanism dictated by the tumor microenvironment (TME). Macrophage Migratory Inhibition Factor (MIF) has emerged as an immunosuppressive factor secreted in the TME. We have previously demonstrated that blockade of the MIF-CD74 signaling on macrophages and dendritic cells restored the anti-tumor immune response against melanoma. Here, we report that inhibition of the MIF-CD74 axis combined with ipilimumab could render resistant melanoma to better respond to anti-CTLA-4 treatment. We provide evidence that blocking the MIF-CD74 signaling potentiates CD8+ T-cells infiltration and drives pro-inflammatory M1 conversion of macrophages in the TME. Furthermore, MIF inhibition resulted in reprogramming the metabolic pathway by reducing lactate production, HIF-1α and PD-L1 expression in the resistant melanoma cells. Melanoma patient data extracted from the TCGA database supports the hypothesis that high MIF expression strongly correlates with poor response to ICB therapy. Our findings provide a rationale for combining anti-CTLA-4 with MIF inhibitors as a potential strategy to overcome resistance to ICB therapy in melanoma, turning a "cold" tumor into a "hot" one mediated by the activation of innate immunity and reprogramming of tumor metabolism and reduced PD-L1 expression in melanoma cells.
    Keywords:  Macrophage Migratory Inhibition Factor; Melanoma; combined modality therapy; immune checkpoint therapy; tumor microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2020.1846915
  5. Curr Opin Pharmacol. 2020 Dec 16. pii: S1471-4892(20)30134-X. [Epub ahead of print]57 60-70
    Aziz IS, McMahon AM, Friedman D, Rabinovich-Nikitin I, Kirshenbaum LA, Martino TA.
      Circadian rhythms follow a 24 h day and night cycle, regulate vital physiological processes, and are especially relevant to cardiovascular growth, renewal, repair, and remodeling. A recent flurry of clinical and experimental studies reveals a profound circadian influence on immune responses in cardiovascular disease. The first section of this review summarizes the importance of circadian rhythms for cardiovascular health and disease. The second section introduces the circadian nature of inflammatory responses. The third section combines these to elucidate a new role for the circadian system, influencing inflammation in heart disease, especially myocardial infarction. Particular focus is on circadian regulation of the NACHT, LRR, and PYD domains-containing protein 3 inflammasome, neutrophils, monocytes/macrophages, and T cells involved in cardiac repair. A role for biological sex is noted. The final section explores circadian influences on inflammation in other major cardiovascular conditions. Circadian regulation of inflammation has profound implications for benefitting the diagnosis, treatment, and prognosis of patients with cardiovascular disease.
    Keywords:  Cytokines; Heart failure; Inflammasome; Macrophages; Myocardial infarction; Neutrophils; T-lymphocytes
    DOI:  https://doi.org/10.1016/j.coph.2020.11.007
  6. Aging (Albany NY). 2020 Dec 22. 12
    Zhang J, Rong Y, Luo C, Cui W.
      Osteoarthritis is a chronic degenerative disease that can lead to restricted activity or even disability. Bone marrow mesenchymal stem cells can repair cartilage damage and treat osteoarthritis via cell therapies or in-tissue engineering. Research has shown that the paracrine mechanism is the main mode of action of mesenchymal stem cells. Exosomes are the smallest known membrane-bound nanovesicles. Exosomes are also important carriers of paracrine delivery agents and promote communication between cells. We demonstrated that bone marrow mesenchymal stem cell-derived exosomes can delay the progression of osteoarthritis. Exosomes alleviate cartilage damage, reduce osteophyte formation and synovial macrophage infiltration, inhibit M1 macrophage production and promote M2 macrophage generation. In synovial fluid, the expression levels of the proinflammatory cytokines, IL-1β, IL-6, and TNF-α were decreased and the release of the anti-inflammatory cytokine, IL-10 was increased. In vitro, macrophages treated with exosomes maintain chondrocytes' chondrogenic characteristics and inhibit hypertrophy. Our results demonstrated that bone marrow mesenchymal stem cell-derived exosomes may relieve osteoarthritis by promoting the phenotypic transformation of synovial macrophages from M1 to M2.
    Keywords:  bone marrow mesenchymal stem cells; exosomes; osteoarthritis; polarization; synovial macrophages
    DOI:  https://doi.org/10.18632/aging.104110
  7. Trends Endocrinol Metab. 2020 Dec 17. pii: S1043-2760(20)30248-4. [Epub ahead of print]
    Blatzer M, Papon N, Delneste Y, Latgé JP.
      It is well known that the intestine absorbs nutrients, electrolytes, and water. Chikina et al. recently demonstrated that it is also able to sense, recognize, and block the absorption of toxins through a very sophisticated interactive cellular cooperation between novel subpopulations of macrophages and epithelial cells.
    Keywords:  fungal toxins; homeostasis; intestine; macrophages; microbiota
    DOI:  https://doi.org/10.1016/j.tem.2020.11.012
  8. Pharmaceutics. 2020 Dec 17. pii: E1222. [Epub ahead of print]12(12):
    Su Y, Gao J, Kaur P, Wang Z.
      Neutrophils and macrophages are major components of innate systems, playing central roles in inflammation responses to infections and tissue injury. If they are out of control, inflammation responses can cause the pathogenesis of a wide range of diseases, such as inflammatory disorders and autoimmune diseases. Precisely regulating the functions of neutrophils and macrophages in vivo is a potential strategy to develop immunotherapies to treat inflammatory diseases. Advances in nanotechnology have enabled us to design nanoparticles capable of targeting neutrophils or macrophages in vivo. This review discusses the current status of how nanoparticles specifically target neutrophils or macrophages and how they manipulate leukocyte functions to inhibit their activation for inflammation resolution or to restore their defense ability for pathogen clearance. Finally, we present a novel concept of hijacking leukocytes to deliver nanotherapeutics across the blood vessel barrier. This review highlights the challenges and opportunities in developing nanotherapeutics to target leukocytes for improved treatment of inflammatory diseases.
    Keywords:  cell targeting; inflammatory diseases; interactions of nanoparticles and cells; macrophages; nanomedicine; neutrophils
    DOI:  https://doi.org/10.3390/pharmaceutics12121222
  9. Obesity (Silver Spring). 2020 Dec 20.
    Wu Y, Shi T, Wang J, He R.
      OBJECTIVE: Adipose tissue macrophages (ATMs) play critical roles in obesity-associated inflammation that contributes to metabolic dysfunction. Talabostat (TB) exerts some therapeutic effects on tumors and obesity. However, it remains unknown whether the metabolic benefits of TB on obesity is dependent on ATM-mediated adipose inflammation.METHODS: Male C57BL/6J mice were fed a normal chow diet (NCD) or a high-fat diet for 12 weeks, and mice were orally administered TB daily at a low dose (0.5 mg/kg).
    RESULTS: Administration of TB to mice fed a high-fat diet significantly improved adiposity and obesity-associated metabolic dysfunction, including glucose intolerance and insulin resistance, hyperlipidemia and hepatic steatosis, which were accompanied by increased whole-body energy expenditure. RNA sequencing analysis revealed extensive alterations in the transcriptome profiles associated with lipid metabolism and immune responses in adipose tissue of obese mice. Notably, TB treatment led to a significant reduction in ATM accumulation and a shift of the activation state of ATMs from the proinflammatory M1-like to the anti-inflammatory M2-like phenotype. Moreover, depletion of ATMs significantly abolished the TB-induced metabolic benefits.
    CONCLUSIONS: Our study demonstrates that TB at a low dose could increase energy expenditure and control ATM-mediated adipose inflammation in obese mice, thereby alleviating obesity and its associated metabolic dysfunction.
    DOI:  https://doi.org/10.1002/oby.23058
  10. Cells. 2020 Dec 17. pii: E2708. [Epub ahead of print]9(12):
    Schippers M, Post E, Eichhorn I, Langeland J, Beljaars L, Malo MS, Hodin RA, Millán JL, Popov Y, Schuppan D, Poelstra K.
      Alkaline phosphatase (AP) activity is highly upregulated in plasma during liver diseases. Previously, we demonstrated that AP is able to detoxify lipopolysaccharide (LPS) by dephosphorylating its lipid A moiety. Because a role of gut-derived LPS in liver fibrogenesis has become evident, we now examined the relevance of phosphate groups in the lipid A moiety in this process. The effects of mono-phosphoryl and di-phosphoryl lipid A (MPLA and DPLA, respectively) were studied in vitro and LPS-dephosphorylating activity was studied in normal and fibrotic mouse and human livers. The effects of intestinal AP were studied in mice with CCL4-induced liver fibrosis. DPLA strongly stimulated fibrogenic and inflammatory activities in primary rat hepatic stellate cells (rHSCs) and RAW264.7 macrophages with similar potency as full length LPS. However, MPLA did not affect any of the parameters. LPS-dephosphorylating activity was found in mouse and human livers and was strongly increased during fibrogenesis. Treatment of fibrotic mice with intravenous intestinal-AP significantly attenuated intrahepatic desmin+- and αSMA+ -HSC and CD68+- macrophage accumulation. In conclusion, the lack of biological activity of MPLA, contrasting with the profound activities of DPLA, shows the relevance of LPS-dephosphorylating activity. The upregulation of LPS-dephosphorylating activity in fibrotic livers and the protective effects of exogenous AP during fibrogenesis indicate an important physiological role of intestinal-derived AP during liver fibrosis.
    Keywords:  alkaline phosphatase; hepatic stellate cells; lipid A; lipopolysaccharide; liver fibrosis
    DOI:  https://doi.org/10.3390/cells9122708
  11. Analyst. 2020 Dec 21.
    Sugiyama T, Hobro AJ, Pavillon N, Umakoshi T, Verma P, Smith N.
      Macrophage uptake and metabolism of fatty acids is involved in a large number of important biological pathways including immune activation and regulation of macrophages, as well as pathological conditions including obesity, atherosclerosis, and others lifestyle diseases. There are few methods available to directly probe both the uptake and later redistribution/metabolism of fatty acids within living cells as well as the potential changes induced within the cells themselves. We use Raman imaging and analysis to evaluate the effects of different fatty acids following their uptake in macrophages. The label-free nature of the methods means that we can evaluate the fatty acid dynamics without modifying endogenous cellular behavior and metabolism.
    DOI:  https://doi.org/10.1039/d0an02077j
  12. Oncotarget. 2020 Dec 08. 11(49): 4554-4569
    Bader J, Carson M, Enos R, Velazquez K, Sougiannis A, Singh U, Becker W, Nagarkatti M, Fan D, Murphy A.
      BACKGROUND: The association between obesity and colorectal cancer (CRC) risk has been well established. This relationship appears to be more significant in men than in women, which may be attributable to sex hormones. However, controlled animal studies to substantiate these claims and the mechanisms involved are lacking.MATERIALS AND METHODS: MC38 murine colon adenocarcinoma cells were injected subcutaneously into high-fat diet (HFD) fed male, female and ovariectomized (OVX) female C57BL/6 mice.
    RESULTS: HFD increased tumor growth (main effect) that was consistent with metabolic perturbations (P < 0.01). HFD OVX mice exhibited the most significant tumor growth compared to HFD male and female mice (p < 0.05) and this was associated with increased subcutaneous adipose tissue (p < 0.05). Further, the subcutaneous adipose tissue depots within HFD OVX mice exhibited more severe macrophage associated inflammation compared to female (P < 0.01), but not male mice. Conditioned media from subcutaneous adipose tissue of HFD OVX contained higher IGF-1 levels compared to male (P < 0.01), but not female mice. Finally, HFD OVX mice had increased M2-like gene expression in their tumor-associated macrophages (TAMs) compared to female mice (P < 0.01).
    CONCLUSIONS: This work provides evidences suggesting adiposity, adipose specific IGF-1, macrophage associated adipose inflammation, and TAMs as potential mechanisms driving obesity-enhanced CRC in females lacking ovarian hormones.
    Keywords:  colorectal cancer; inflammation; macrophage; metabolism; obesity
    DOI:  https://doi.org/10.18632/oncotarget.27832