Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype

AbstractObesity is associated with inflammatory macrophages in insulin responsive tissues and the resulting inflammatory response is a major contributor to insulin resistance. In insulin-producing pancreatic islets, the intra-islet accumulation of macrophages is observed in patients of type 2 diabetes (T2D), but such has not been investigated in obese individuals. Here, we show that pro-inflammatory cytokines (IL-1β, IL-6, and TNF), anti-inflammatory cytokines (IL-10 and TGF-β) and macrophage polarization markers (CD11c, CD163, and NOS2) were expressed in isolated human islets from non-diabetic donors. Clodronate-mediated depletion of resident macrophages revealed expression of IL1B and IL10 mostly from macrophages, while IL6, TNF, and TGFB1 came largely from a non-macrophage origin in human islets. NOS2 expression came exclusively from non-macrophage cells in non-obese individuals, while it originated also from macrophages in obese donors. Macrophage marker expression of CD68, CD163, and ITGAX was unchanged in islets of non-obese control and obese cohorts. In contrast, IL1B and NOS2 were significantly increased in islets from obese, compared to non-obese individuals, implying a more inflammatory macrophage phenotype in islets in obesity. Our study shows elevated macrophage-associated inflammation in human islets in obesity, which could be an initiating factor to the pro-inflammatory intra-islet milieu and contribute to the higher susceptibility to T2D in obese individuals.

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Keratin biomaterials augment anti-inflammatory macrophage phenotype in vitro

Acta Biomaterialia ◽

10.1016/j.actbio.2017.10.042 ◽

2018 ◽

Vol 66 ◽

pp. 213-223 ◽

Cited By ~ 18

Author(s):

Michele Waters ◽

Pamela VandeVord ◽

Mark Van Dyke

Keyword(s):

Macrophage Phenotype ◽

Anti Inflammatory ◽

Inflammatory Macrophage

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IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 and other diseases with tissue inflammation

10.1101/2020.08.05.238360 ◽

2020 ◽

Cited By ~ 3

Author(s):

Fan Zhang ◽

Joseph R. Mears ◽

Lorien Shakib ◽

Jessica I. Beynor ◽

Sara Shanaj ◽

...

Keyword(s):

Immune Cell ◽

Ex Vivo ◽

Inflammatory Diseases ◽

Macrophage Phenotype ◽

Tnf Α ◽

Key Driver ◽

Ifn Γ ◽

Immunomodulatory Therapies ◽

Disease Analysis ◽

Inflammatory Macrophage

AbstractImmunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that an FCN1+ inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that a CXCL10+ CCL2+ inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such as GBP1, STAT1, and IL1B. We found that the CXCL10+ CCL2+ macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF-α and IFN-γ ex vivo. Our findings suggest that IFN-γ, alongside TNF-α, might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.

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eIF6 Promotes Inﬂammatory Macrophage Phenotype, Foam Cell Formation and Atherosclerosise

10.21203/rs.3.rs-820763/v1 ◽

2021 ◽

Author(s):

Junnian Zheng ◽

Renjin Chen ◽

Xuemei Xian ◽

xiaoqiang Zhan ◽

Jiajia Chang ◽

...

Keyword(s):

Foam Cell ◽

Cell Formation ◽

Western Diet ◽

Initiation Factor ◽

Immunofluorescent Staining ◽

Foam Cell Formation ◽

Macrophage Phenotype ◽

Anti Inflammatory ◽

Inflammatory Macrophage ◽

Novel Therapeutic

Abstract Background：Atherosclerosis is a chronic inflammatory disease, caused by accumulation of lipid-laden and inflammatory macrophages in the artery wall. Understanding its molecular mechanisms and developing novel therapeutic targets to promote atherosclerotic regression is an important clinical goal.Methods : ApoE-/- and eIF6+/-/ApoE-/- mice were fed Western diet (WD) for 16 weeks. Molecular biology technology were performed to analyze the differences between them.Results: The mechanism by which Eukaryotic initiation factor 6 (eIF6) affects macrophages and atherosclerosis remains to be elucidated. Western blotting and real-time polymerase chain reaction (PCR ) analysis indicated significantly higher expression levels of eIF6 than those in the control in RAW264.7 cells induced by Lipopolysaccharide (LPS) and Interleukin-4 (IL4). We constructed eIF6+/-/ApoE-/- mice, the hematoxylin (HE) and Oil Red O staining analysis indicated that these mice showed a significant decrease in atherosclerotic lesion formation increased anti-inﬂammatory cell content in aortas, and reduced necrotic core content compared with ApoE-/- mice on a western diet for 16 weeks. eIF6 deficiency suppressed foam cell formation and promoted the anti-inﬂammatory macrophage phenotype in primary macrophages. More anti-inflammatory populations were observed in blood and atherosclerotic aortas of eIF6+/- ApoE-/- mice by flow cytometry. Immunofluorescent staining analysis obtained the same results.Conclusions: eIF6 deficiency protects against atherosclerosis by promoting the anti-inﬂammatory macrophage phenotype and reducing macrophage uptake of low-density lipoprotein (LDL), indicating that new insight into eIF6 may reveal a potential novel therapeutic target for the resolution of inflammation in atherosclerosis.

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