Gene dosage-dependent negative regulatory role of ?-arrestin-2 in polymicrobial infection-induced inflammation.

ABSTRACT: ?-arrestin-2 (?-arr2) is a scaffolding protein of the arrestin family with a wide variety of cellular functions. Recent studies have demonstrated differential roles for ?-arr2 in inflammation following endotoxemia and cecal ligation and puncture (CLP) models of sepsis. Because CLP-induced inflammation involves response to fecal contents and necrotic cecum in addition to microbial challenge, in this study, we examined the role of ?-arr2 in an exclusively polymicrobial infection (PMI) model. In addition, we examined the role of gene dosage of ?-arr2 in polymicrobial sepsis. Our studies demonstrate that ?-arr2 is a negative regulator of systemic inflammation in response to polymicrobial infection and that one allele is sufficient for this process. Our results further reveal that loss of ?-arr2 leads to increased neutrophil sequestration and overt inflammation specifically in the lungs following polymicrobial infection. Consistent with this, specific NF-?B and mitogen-activated protein kinase (MAPK) signaling pathways were differentially activated in the ?-arr2 knockout (KO) mice lungs compared to the wild type (WT) following PMI. Associated with enhanced inflammation in the KO mice, PMI-induced mortality was also significantly higher in KO mice than in WT mice. To understand the differential role of ?-arr2 in different sepsis models, we used cell culture systems to evaluate inflammatory cytokine production following endotoxin and polymicrobial stimulation. Our results demonstrate cell-type- as well as stimulus-specific roles for ?-arr2 in inflammation. Taken together, our results reveal a negative regulatory role for ?-arr2 in polymicrobial infection-induced inflammation and further demonstrate that one allele of ?-arr2 is sufficient to mediate most of these effects.

SUBMITTER: Sharma D 

PROVIDER: S-EPMC3719563 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature