Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages

Abstract

Macrophages consist of at least two subgroups, M1 and M2 (refs 1-3). Whereas M1 macrophages are proinflammatory and have a central role in host defence against bacterial and viral infections, M2 macrophages are associated with responses to anti-inflammatory reactions, helminth infection, tissue remodelling, fibrosis and tumour progression. Trib1 is an adaptor protein involved in protein degradation by interacting with COP1 ubiquitin ligase. Genome-wide association studies in humans have implicated TRIB1 in lipid metabolism. Here we show that Trib1 is critical for the differentiation of F4/80(+)MR(+) tissue-resident macrophages--that share characteristics with M2 macrophages (which we term M2-like macrophages)--and eosinophils but not for the differentiation of M1 myeloid cells. Trib1 deficiency results in a severe reduction of M2-like macrophages in various organs, including bone marrow, spleen, lung and adipose tissues. Aberrant expression of C/EBPα in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation. Unexpectedly, mice lacking Trib1 in haematopoietic cells show diminished adipose tissue mass accompanied by evidence of increased lipolysis, even when fed a normal diet. Supplementation of M2-like macrophages rescues the pathophysiology, indicating that a lack of these macrophages is the cause of lipolysis. In response to a high-fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine gene induction. Collectively, these results demonstrate that Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages.

Neutrophils alleviate fibrosis in the CCl4‐induced mouse chronic liver injury model

“…Even before the administration of CCl 4 , Ly6G + neutrophils were clearly increased in Trib1 KO liver whereas F4/80 + macrophages were slightly reduced, consistent with a previous report12 (Fig. 2A; http://onlinelibrary.wiley.com/doi/10.1002/hep4.1178/full).…”

“…Loss of Trib1 was previously shown to decrease tissue‐resident M2‐like macrophages and eosinophils and increase neutrophils by altering the expression level of C/EBPα in an E3‐ubiquitin ligase constitutive photomorphogenic 1‐dependent manner 12. Because macrophages have been implicated in liver fibrosis, we investigated liver fibrosis in Trib1 ‐deficient mice.…”

“…Because M2 macrophages have been considered to be profibrotic by producing TGF‐β and lack of Trib1 was previously shown to decrease tissue resident M2‐like macrophages and increase neutrophils,12 we hypothesized that liver fibrosis would be altered in Trib1 KO mice. Although macrophages in Trib1 KO liver were slightly decreased, no significant change was observed in the expression of fibrogenic TGF‐β at 48 hours after either a single dose or continuous administration of CCl 4 (http://onlinelibrary.wiley.com/doi/10.1002/hep4.1178/full; Fig 1C).…”

“…Thus, Trib1 deficiency may exhibit a phenotype similar to overexpression of C/EBPα. In fact, Satoh et al showed that Trib1 KO increased the neutrophil population in the spleen whereas M2‐like macrophages and eosinophils were reduced 12. As M2 macrophages are anti‐inflammatory and promote tissue repair by producing fibrogenic factors, we were interested in evaluating liver fibrosis in the Trib1 ‐deficient mouse.…”

TRIB1 (tribbles pseudokinase 1)

“…When mice are fed a high fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance and a pro-inflammatory cytokine induction (Satoh, et al 2013).…”