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CD200 increases alternatively activated macrophages through cAMP-response element binding protein - C/EBP-beta signaling.


ABSTRACT: The concept of macrophage polarization toward different phenotypes after CNS injury has been increasingly discussed. Here, we propose that CD200 treatment may help shift pro-inflammatory macrophages to an arginase 1 (Arg1)-, transglutaminase 2 (TGM2)-, and transforming growth factor beta 1 (TGF-?)-positive phenotype. Rat macrophages were stimulated by interferon ? and lipopolysaccharide (LPS) to induce pro-inflammatory phenotypes. Treatment with human CD200-Fc up-regulated expression levels of alternatively activated M2-like markers such as Arg1 and TGM2 but suppressed pro-inflammatory M1-like markers such as toll-like receptor 4, interleukin 1 beta (IL-1?), IL-6, and GM-CSF. Concomitantly, CD200-Fc enhanced (CCAAT/enhancer-binding protein) C/EBP-beta promoter activity, whereas NF-?B activity was suppressed. Treatment with CD200-Fc also up-regulated potentially beneficial TGF-? expression in macrophages. When C/EBP-beta signaling was suppressed with siRNA, the effect of CD200-Fc on Arg1, TGM2 and TGF-? up-regulation was canceled. Taken together, these data provide proof-of-principle that targeting CD200 signaling may be a novel therapeutic approach to shift macrophages toward M2-like polarization via modulating cAMP-response element binding protein-C/EBP-beta transcriptional activity. We showed that CD200 treatment decreased pro-inflammatory cytokines (IL-1?, IL-6, and GM-CSF) along with suppressed inflammatory NF-?B activity in pro-inflammatory M?. On the other hand, CD200 increased Arg1, TGM2, and TGF-? production through CREB-C/EBP? signaling. We think that these findings provide proof-of-concept that CD200 signaling may play a key role in regulating macrophage polarization toward anti-inflammatory phenotypes.

SUBMITTER: Hayakawa K 

PROVIDER: S-EPMC4755817 | BioStudies | 2016-01-01

REPOSITORIES: biostudies

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