title: Nonhematopoietic β-Arrestin-1 inhibits inflammation in a murine model of polymicrobial sepsis.
abstract: β-Arrestin-1 (βArr1), a scaffolding protein critical in G-protein coupled receptor desensitization has more recently been found to be important in the pathogenesis of various inflammatory diseases. We sought to understand the role of βArr1 in sepsis pathogenesis using a mouse model of polymicrobial sepsis. Although in previous studies we established that βArr1 deficiency protects mice from endotoxemia, here we demonstrate that the absence of βArr1 remarkably renders mice more susceptible to mortality in polymicrobial sepsis. In accordance with the mortality pattern, early production of inflammatory mediators was markedly enhanced in βArr1 knockout mice systemically and locally in various organs. In addition, enhanced inflammation in the heart was associated with increased NFκB activation. Compared to these effects, immune cell infiltration, thymic apoptosis, and immune suppression during polymicrobial sepsis were unaffected by a deficiency of βArr1. Additionally, enhanced inflammation and consequent higher mortality were not observed in heterozygous mice, suggesting that one allele of βArr1 was sufficient for this protective negative regulatory role. We further demonstrate that, unexpectedly, βArr1 in nonhematopoietic cells is critical and sufficient for inhibiting sepsis-induced inflammation, whereas hematopoietic βArr1 is likely redundant. Taken together, our results reveal a novel and previously unrecognized negative regulatory role of the nonhematopoietic βArr1 in sepsis-induced inflammation.
authors.affiliation: Graduate Programs in Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan.
authors.forename: Deepika
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Comparative Medicine and Integrative Biology, Michigan State University, East Lansing, Michigan.
authors.forename: Nandakumar
authors.initials: N
authors.lastname: Packiriswamy
authors.affiliation: Graduate Programs in Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan.
authors.forename: Ankit
authors.initials: A
authors.lastname: Malik
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lucas
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan. Electronic address: paramesw@msu.edu.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Parameswaran
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605255:Arrb1 protein, mouse; D019390:Arrestins; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins