G-protein-coupled receptor kinase-5 mediates inflammation but does not regulate cellular infiltration or bacterial load in a polymicrobial sepsis model in mice

Nandakumar Packiriswamy, Taehyung Lee, Pongali B. Raghavendra, Haritha Durairaj, Hongbing Wang, Narayanan Parameswaran

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    Abstract

    NFκB-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 NFκB pathway. We hypothesized that GRK5 via NFκB 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 NFκB activation in sepsis-induced inflammation, we assessed the levels of IκBα phosphorylation and expression of NFκB-dependent genes in the liver in the two genotypes. Both IκBα 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.

    Original languageEnglish
    Pages (from-to)401-413
    Number of pages13
    JournalJournal of Innate Immunity
    Volume5
    Issue number4
    DOIs
    Publication statusPublished - 06-2013

    Fingerprint

    G-Protein-Coupled Receptor Kinase 5
    Bacterial Load
    Sepsis
    Inflammation
    Punctures
    Knockout Mice
    Ligation
    Phosphorylation
    Apoptosis
    Thymocytes
    Corticosterone

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy

    Cite this

    Packiriswamy, Nandakumar ; Lee, Taehyung ; Raghavendra, Pongali B. ; Durairaj, Haritha ; Wang, Hongbing ; Parameswaran, Narayanan. / G-protein-coupled receptor kinase-5 mediates inflammation but does not regulate cellular infiltration or bacterial load in a polymicrobial sepsis model in mice. In: Journal of Innate Immunity. 2013 ; Vol. 5, No. 4. pp. 401-413.
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    abstract = "NFκB-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 NFκB pathway. We hypothesized that GRK5 via NFκB 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 NFκB activation in sepsis-induced inflammation, we assessed the levels of IκBα phosphorylation and expression of NFκB-dependent genes in the liver in the two genotypes. Both IκBα 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.",
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    G-protein-coupled receptor kinase-5 mediates inflammation but does not regulate cellular infiltration or bacterial load in a polymicrobial sepsis model in mice. / Packiriswamy, Nandakumar; Lee, Taehyung; Raghavendra, Pongali B.; Durairaj, Haritha; Wang, Hongbing; Parameswaran, Narayanan.

    In: Journal of Innate Immunity, Vol. 5, No. 4, 06.2013, p. 401-413.

    Research output: Contribution to journalArticle

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    AU - Packiriswamy, Nandakumar

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    AU - Raghavendra, Pongali B.

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