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NK but Not CD1-Restricted NKT Cells Facilitate Systemic Inflammation during Polymicrobial Intra-Abdominal Sepsis¹

Anthony O. Etogo^*, Jesus Nunez^*, Cheng Y. Lin^*, Tracy E. Toliver-Kinsky^*, and Edward R. Sherwood^2,*,

^* Department of Anesthesiology, Department of Microbiology and Immunology, and Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, and Shriners Hospitals for Children, Galveston, TX 77555

Evidence suggests that NK and NKT cells contribute to inflammation and mortality during septic shock caused by cecal ligation and puncture (CLP). However, the specific contributions of these cell types to the pathogenesis of CLP-induced septic shock have not been fully defined. The goal of the present study was to determine the mechanisms by which NK and NKT cells mediate the host response to CLP. Control, NK cell-deficient, and NKT cell-deficient mice underwent CLP. Survival, cytokine production, and bacterial clearance were measured. NK cell trafficking and interaction with myeloid cells was also studied. Results show that mice treated with anti-asialoGM1 (NK cell deficient) or anti-NK1.1 (NK/NKT cell deficient) show less systemic inflammation and have improved survival compared with IgG-treated controls. CD1 knockout mice (NKT cell deficient) did not demonstrate decreased cytokine production or improved survival compared with wild type mice. Trafficking studies show migration of NK cells from blood and spleen into the inflamed peritoneal cavity where they appear to facilitate the activation of peritoneal macrophages (F4-80⁺GR-1^–) and F4-80⁺Gr-1⁺ myeloid cells. These findings indicate that NK but not CD1-restricted NKT cells contribute to acute CLP-induced inflammation. NK cells appear to mediate their proinflammatory functions during septic shock, in part, by migration into the peritoneal cavity and amplification of the proinflammatory activities of specific myeloid cell populations. These findings provide new insights into the mechanisms used by NK cells to facilitate acute inflammation during septic shock.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants R01 GM66885 from the National Institutes of Health and 8780 from the Shriners of North America.

² Address correspondence and reprint requests to Dr. Edward R. Sherwood, Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555. E-mail address: ersherwo{at}utmb.edu

³ Abbreviations used in this paper: CLP, cecal ligation and puncture; CD1KO, CD1 knockout; MFI, mean fluorescence intensity.

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