Journal
JOURNAL OF INNATE IMMUNITY
Volume 5, Issue 4, Pages 401-413Publisher
KARGER
DOI: 10.1159/000347002
Keywords
Apoptosis; Cytokines; Host defense; Immune response; Macrophages; Sepsis; Septic shock; Toll-like receptor
Categories
Funding
- NIH [HL095637, AR055726, AR056680]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL095637] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R21AR055726, R01AR056680] Funding Source: NIH RePORTER
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NF kappa B-dependent signaling is an important modulator of inflammation in several diseases including sepsis. G-protein-coupled receptor kinase-5 (GRK5) is an evolutionarily conserved regulator of the NF kappa B pathway. We hypothesized that GRK5 via NF kappa B regulation plays an important role in the pathogenesis of sepsis. To test this we utilized a clinically relevant polymicrobial sepsis model in mice that were deficient in GRK5. We subjected wild-type (WT) and GRK5 knockout (KO) mice to cecal ligation and puncture (CLP)-induced polymicrobial sepsis and assessed the various events in sepsis pathogenesis. CLP induced a significant inflammatory response in the WT and this was markedly attenuated in the KO mice. To determine the signaling mechanisms and the role of NF kappa B activation in sepsis-induced inflammation, we assessed the levels of I kappa Ba phosphorylation and expression of NF kappa B-dependent genes in the liver in the two genotypes. Both I kappa Ba phosphorylation and gene expression were significantly inhibited in the GRK5 KO compared to the WT mice. Interestingly, however, GRK5 did not modulate either immune cell infiltration (to the primary site of infection) or local/systemic bacterial load subsequent to sepsis induction. In contrast GRK5 deficiency significantly inhibited sepsis-induced plasma corticosterone levels and the consequent thymocyte apoptosis in vivo. Associated with these outcomes, CLP-induced mortality was significantly prevented in the GRK5 KO mice in the presence of antibiotics. Together, our studies demonstrate that GRK5 is an important regulator of inflammation and thymic apoptosis in polymicrobial sepsis and implicate GRK5 as a potential molecular target in sepsis. Copyright (C) 2013S. Karger AG, Basel
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