Expression of Scavenger Receptor-AI Promotes Alternative Activation of Murine Macrophages to Limit Hepatic Inflammation and Fibrosis

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 (M phi) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for M/in limiting hepatic inflammation or resolving liver damage have not been fully understood. In this report, we demonstrate that expression of C-type lectin receptor scavenger receptor-AI (SR-AI) is crucial for promoting M phi-like M/activation and polarization during hepatic inflammation. Liver M phi uniquely up-regulated SR-AI during hepatotropic viral infection and displayed increased expression of alternative M phi activation markers, such as YM-1, arginase-1, and interleukin-10 by activation of mer receptor tyrosine kinase associated with inhibition of mammalian target of rapamycin. Expression of these molecules was reduced on M phi obtained from livers of infected mice deficient for the gene encoding SR-AI (msr1). Furthermore, in vitro studies using an SR-AI-deficient M phi 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 M phi conferred protection against fibrosis in these mice. Conclusion: SR-AI expression on liver M phi promotes recovery from infection-induced tissue damage by mediating a switch to a proresolving M/polarization state.