| First Author | Sharma D | Year | 2013 |
| Journal | Infect Immun | Volume | 81 |
| Issue | 8 | Pages | 3035-44 |
| PubMed ID | 23753627 | Mgi Jnum | J:199834 |
| Mgi Id | MGI:5505362 | Doi | 10.1128/IAI.00653-13 |
| Citation | Sharma D, et al. (2013) Gene dosage-dependent negative regulatory role of beta-arrestin-2 in polymicrobial infection-induced inflammation. Infect Immun 81(8):3035-44 |
| abstractText | beta-arrestin-2 (beta-arr2) is a scaffolding protein of the arrestin family with a wide variety of cellular functions. Recent studies have demonstrated differential roles for beta-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 beta-arr2 in an exclusively polymicrobial infection (PMI) model. In addition, we examined the role of gene dosage of beta-arr2 in polymicrobial sepsis. Our studies demonstrate that beta-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 beta-arr2 leads to increased neutrophil sequestration and overt inflammation specifically in the lungs following polymicrobial infection. Consistent with this, specific NF-kappaB and mitogen-activated protein kinase (MAPK) signaling pathways were differentially activated in the beta-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 beta-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 beta-arr2 in inflammation. Taken together, our results reveal a negative regulatory role for beta-arr2 in polymicrobial infection-induced inflammation and further demonstrate that one allele of beta-arr2 is sufficient to mediate most of these effects. |
