| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Division of Dermatology and
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;
Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH 03755;
Department of Biology, California Institute of Technology, Pasadena, CA 91125; and
¶ Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
IL-1R activation is required for neutrophil recruitment in an effective innate immune response against Staphylococcus aureus infection. In this study, we investigated the mechanism of IL-1R activation in vivo in a model of S. aureus infection. In response to a S. aureus cutaneous challenge, mice deficient in IL-1β, IL-1
/IL-1β, but not IL-1, developed larger lesions with higher bacterial counts and had decreased neutrophil recruitment compared with wild-type mice. Neutrophil recruitment and bacterial clearance required IL-1β expression by bone marrow (BM)-derived cells and not by non-BM-derived resident cells. In addition, mice deficient in the inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) had the same defects in neutrophil recruitment and host defense as IL-1β-deficient mice, demonstrating an essential role for the inflammasome in mediating the production of active IL-1β to promote neutrophil recruitment in host defense against S. aureus. This finding was further supported by the ability of recombinant active IL-1β to control the infection and promote bacterial clearance in IL-1β-deficient mice. These studies define a key host defense circuit where inflammasome-mediated IL-1β production by BM-derived cells signals IL-1R on non-BM-derived resident cells to activate neutrophil recruitment in the innate immune response against S. aureus in vivo.
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 in part by Grants R01 AI22553, R01 AI47868, R01 AR40312 (to R.L.M.), R01 AI056154, R01 CA87924, and R01 AI052359 (to G.C.), K08 AI62985 (to L.S.M.) and in part by the University of California Los Angeles Small Animal Imaging Resource Program National Institutes of Health (NIH)-National Cancer Institute 2U24 CA092865 Cooperative Agreement from the NIH. Ruth L. Kirschstein Research Service Award GM 007185 also supported this work (to E.M.P.).
2 L.S.M. and E.M.P. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Robert L. Modlin, David Geffen School of Medicine, Center for Health Sciences, UCLA, 52-121, 10833 Le Conte Avenue, Los Angeles, CA 90095; E-mail address: rmodlin{at}mednet.ucla.edu or Dr. Genhong Cheng, David Geffen School of Medicine, Center for Health Sciences, UCLA, 52-121, 10833 Le Conte Avenue, Los Angeles, CA 90095; E-mail address: genhongc{at}microbio.ucla.edu
4 Abbreviations used in this paper: wt, wild type; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BM, bone marrow; BMM, BM-derived macrophage; TSB, tryptic soy broth; MPO, myeloperoxidase.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
