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: Deepika Sharma, Ankit Malik, Eunhee Lee, Robert A Britton, Narayanan Parameswaran
• Journal: Infection and immunity (Infect Immun) Vol. 81 Issue 8 Pg. 3035-44 (Aug 2013) ISSN: 1098-5522 [Electronic] United States
• PMID: 23753627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Arrb2 protein, mouse
• Arrestins
• beta-Arrestin 2
• beta-Arrestins

Topics

• Animals
• Arrestins (genetics, immunology)
• Blotting, Western
• Coinfection (genetics, immunology)
• Flow Cytometry
• Gene Dosage
• Inflammation (genetics, immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Reverse Transcriptase Polymerase Chain Reaction
• Sepsis (genetics, immunology)
• Signal Transduction (genetics, immunology)
• beta-Arrestin 2
• beta-Arrestins