Regulation of lymphocyte trafficking by CXC chemokine receptor 3 during septic shock.

Herzig DS, Driver BR, Fang G, Toliver-Kinsky TE, Shute EN, Sherwood ER
Am J Respir Crit Care Med. 2012 185 (3): 291-300

PMID: 22135342 · PMCID: PMC3297107 · DOI:10.1164/rccm.201108-1560OC

RATIONALE - Lymphocytes have been shown to facilitate systemic inflammation and physiologic dysfunction in experimental models of severe sepsis. Our previous studies show that natural killer (NK) cells migrate into the peritoneal cavity during intraabdominal sepsis, but the trafficking of NKT and T lymphocytes has not been determined. The factors that regulate lymphocyte trafficking during sepsis are currently unknown.

OBJECTIVES - To ascertain the importance of CXC chemokine receptor 3 (CXCR3) as a regulator of lymphocyte trafficking during sepsis and determine the contribution of CXCR3-mediated lymphocyte trafficking to the pathogenesis of septic shock.

METHODS - Lymphocyte trafficking was evaluated in control and CXCR3-deficient mice using flow cytometry during sepsis caused by cecal ligation and puncture (CLP). Survival, core temperature, cytokine production, and bacterial clearance were measured as pathobiological endpoints.

MEASUREMENTS AND MAIN RESULTS - This study shows that concentrations of the CXCR3 ligands CXCL9 (monokine induced by interferon γ, MIG) and CXCL10 (interferon γ-induced protein 10, IP-10) increase in plasma and the peritoneal cavity after CLP, peak at 8 hours after infection, and are higher in the peritoneal cavity than in plasma. The numbers of CXCR3(+) NK cells progressively decreased in spleen after CLP with a concomitant increase within the peritoneal cavity, a pattern that was ablated in CXCR3-deficient mice. CXCR3-dependent recruitment of T cells was also evident at 16 hours after CLP. Treatment of mice with anti-CXCR3 significantly attenuated CLP-induced hypothermia, decreased systemic cytokine production, and improved survival.

CONCLUSIONS - CXCR3 regulates NK- and T-cell trafficking during sepsis and blockade of CXCR3 attenuates the pathogenesis of septic shock.

MeSH Terms (16)

Animals Cell Movement Chemokine CXCL9 Chemokine CXCL10 Cytokines Enzyme-Linked Immunosorbent Assay Female Flow Cytometry Intraabdominal Infections Killer Cells, Natural Mice Mice, Inbred C57BL Natural Killer T-Cells Receptors, CXCR3 Shock, Septic T-Lymphocytes

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