title: Gene dosage-dependent negative regulatory role of β-arrestin-2 in polymicrobial infection-induced inflammation.
abstract: β-arrestin-2 (β-arr2) is a scaffolding protein of the arrestin family with a wide variety of cellular functions. Recent studies have demonstrated differential roles for β-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 β-arr2 in an exclusively polymicrobial infection (PMI) model. In addition, we examined the role of gene dosage of β-arr2 in polymicrobial sepsis. Our studies demonstrate that β-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 β-arr2 leads to increased neutrophil sequestration and overt inflammation specifically in the lungs following polymicrobial infection. Consistent with this, specific NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways were differentially activated in the β-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 β-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 β-arr2 in inflammation. Taken together, our results reveal a negative regulatory role for β-arr2 in polymicrobial infection-induced inflammation and further demonstrate that one allele of β-arr2 is sufficient to mediate most of these effects.
authors.affiliation: Department of Physiology and Division of Pathology, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Sharma
authors.forename: Ankit
authors.initials: A
authors.lastname: Malik
authors.forename: Eunhee
authors.initials: E
authors.lastname: Lee
authors.forename: Robert A
authors.initials: RA
authors.lastname: Britton
authors.forename: Narayanan
authors.initials: N
authors.lastname: Parameswaran
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics* / Q000276:immunology; D015153:Blotting, Western; D060085:Coinfection / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D018628:Gene Dosage; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605258:Arrb2 protein, mouse; D019390:Arrestins; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins