title: Role of myeloid-specific G-protein coupled receptor kinase-2 in sepsis.
abstract: Previous studies have implicated a critical role for G-protein coupled receptor kinase-2 (GRK2) in sepsis owing to its ability to regulate inflammatory response and chemotaxis of immune cells. We therefore, hypothesized that deletion of GRK2 in myeloid cells would significantly modulate the pathogenesis of polymicrobial sepsis. To test this hypothesis, we induced cecal ligation and puncture (CLP), in mice with myeloid-specific deletion of GRK2 and the corresponding GRK2 wild type littermates and determined the inflammatory response (IL-6 and IL-10), immune cell infiltration, bacterial load and survival. Six hours after surgery, plasma IL-6 and IL-6:IL-10 ratios were significantly enhanced in the GRK2 knockouts compared to the GRK2 wild type mice. Compared to these effects, IL-6was significantly elevated in the bronchoalveolar lavage but not in the peritoneal fluid of the GRK2 knockout mice. On the other hand, peritoneal IL-10 was significantly elevated in the GRK2 knockout mice compared to the GRK2 wild type. Even though GRK2 knockout mice exhibited an exaggerated cytokine response, there was no difference in immune cell infiltration into the primary site of infection or in bacterial clearance when compared between the GRK2 wild type and GRK2 knockout mice after surgery. Furthermore, in spite of the enhanced pro-inflammatory profile early after surgery, there was only a modest increase in mortality in the GRK2 knockout compared to the GRK2 wild type mice after CLP. Together, our studies demonstrate that myeloid-specific knockout of GRK2 renders the mice more susceptible to an early pro-inflammatory state. However, myeloid-specific GRK2 is not involved in immune cell infiltration to the primary site of infection or in bacterial clearance and does not significantly modulate mortality in the cecal ligation puncture model of polymicrobial sepsis.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, USA.
authors.forename: Sitaram
authors.initials: S
authors.lastname: Parvataneni
authors.forename: Babu
authors.initials: B
authors.lastname: Gonipeta
authors.forename: Nandakumar
authors.initials: N
authors.lastname: Packiriswamy
authors.forename: Taehyung
authors.initials: T
authors.lastname: Lee
authors.forename: Haritha
authors.initials: H
authors.lastname: Durairaj
authors.forename: Narayanan
authors.initials: N
authors.lastname: Parameswaran