Expression of scavenger receptor‐AI promotes alternative activation of murine macrophages to limit hepatic inflammation and fibrosis

Abstract

The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis and hepatocellular carcinoma. Macrophages (Mϕ) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mϕ in limiting hepatic inflammation or resolving liver damage have not been fully understood. In this report, we demonstrate that the expression of C-type lectin receptor scavenger receptor-AI (SR-AI) is crucial for promoting M2-like Mϕ activation and polarization during hepatic inflammation. Liver Mϕ uniquely upregulated SR-AI during hepatotropic viral infection and displayed increased expression of alternative Mϕ activation markers such as YM-1, arginase-1, and IL-10 via the activation of Mertk associated with inhibition of mTOR. The expression of these molecules was reduced on Mϕ obtained from the livers of infected mice deficient for the gene encoding SR-AI (msr1). Furthermore, in vitro studies using an SR-AI-deficient Mϕ cell line revealed impeded M2 polarization and decreased phagocytic capacity. Direct stimulation with virus was sufficient to activate M2 gene expression in the wild type (WT) cell line but not in the knockdown cell line. Importantly, tissue damage and fibrosis were exacerbated in SR-AI−/− mice following hepatic infection and adoptive transfer of WT bone marrow derived Mϕ conferred protection against fibrosis in these mice. Conclusion: SR-AI expression on liver Mϕ promotes recovery from infection-induced tissue damage by mediating a switch to a pro-resolving Mϕ polarization state.

Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy

“…Although MSR1 has been implicated in recognition of viral nucleic acids, activation of type I interferon 4, 5 , macrophage adherence 6 , M2 macrophage polarization 7 , and activation of neutrophil-mediated complement 8 , its molecular mechanism of action remains elusive. In the current study, we demonstrate a critical role for MSR1 in controlling CHIKV pathogenesis and provide several lines of evidence showing how MSR1 participates in autophagy.…”

“…CHIKV was propagated in Vero cells to a titer of ∼10 7 plaque forming units (PFU)/ml and prepared in 50µl of sterile 1% gelatin in phosphate buffered saline (PBS) for injection. Briefly, age-and sex-matched wild type and specific gene deleted mice (>8 weeks old) were infected with 5×10 4 PFU of La Reunion strain LR2006-OPY1 at the ventral side of a hind foot subcutaneously.…”

“…MSR1 could recognize extracellular viral nucleic acids, mediating their endocytosis and presenting them to TLR3/9, thereby triggering a type I interferon (IFN-I) response in both infected and uninfected cells 4, 5 . MSR1 limits herpes simplex virus 1 infection likely by regulating macrophage adherence in vivo 6 , whereas it controls adenovirus type 5-elicited hepatic inflammation and fibrosis by promoting M2 macrophage polarization 7 . MSR1 could contribute to pathogenesis of murine hepatitis virus-induced fulminant hepatitis by activating neutrophil-mediated complement 8 .…”

Human Scavenger Receptor A1-Mediated Inflammatory Response to Silica Particle Exposure Is Size Specific

“…It has been reported that MerTK activation leads to inhibition of the mTOR pathway and SR-A1-mediated activation of macrophages (44). Inhibition of the mTOR pathway enhances the effects of pro-inflammatory cytokines via NF-κB in phagocytic cells after bacterial stimulation (45) and of caspase-1 during endotoxin-mediated shock (46).…”

Dental Follicle Stem Cells Ameliorate Lipopolysaccharide-Induced Inflammation by Secreting TGF-β3 and TSP-1 to Elicit Macrophage M2 Polarization

“…4B). The macrophage polarization was further investigated using real-time PCR and western blot for the prototypical M1 and M2 markers, inducible nitric oxide synthase (iNOS) and Arg-1 [42]. When cultured in DFSC-CM with LPS stimuli, macrophages exhibited significant upregulation of Arg-1 and downregulation of iNOS, whereas macrophages cultured in Ham's F-12K medium with LPS infection expressed high levels of iNOS but not Arg-1 at both the transcriptional and translational levels (Fig.…”