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Neutrophil Chemokines KC and Macrophage-Inflammatory Protein-2 Are Newly Synthesized by Tissue Macrophages Using Distinct TLR Signaling Pathways¹

Leukocyte Adhesion Laboratory, Cancer Research United Kingdom, London Research Institute, London, United Kingdom

Neutrophils are the first immune cells to migrate into infected tissue sites. Therefore an important step in the initiation of an immune response is the synthesis of the neutrophil-recruiting chemokines. In this in vivo study in mice, we show that resident tissue macrophages are the source of the major neutrophil chemoattractants, KC and MIP-2. Synthesis of these chemokines is rapidly regulated at the transcriptional level by signaling through TLR2, TLR3, and TLR4 that have diverse specificities for pathogens. The major and alternative TLR signaling pathways are characterized by the adaptor proteins MyD88 or TRIF, respectively. KC and MIP-2 are both produced by signaling through MyD88. However MIP-2, but not KC, is also synthesized through the TRIF adaptor protein, identifying it as a new product of this alternative pathway. Use of both pathways by TLR4 ensures maximal levels of KC and MIP-2 that lead to robust neutrophil recruitment. However the MIP-2 generated exclusively by the TRIF pathway is still sufficient to cause an influx of neutrophils. In summary we show that TLR signaling by tissue macrophages directly controls the synthesis of neutrophil-attracting chemokines that are essential for the earliest recruitment step in the innate immune response to microbial challenge.

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 the Cancer Research United Kingdom.

² Current address: Division of Immune Cell Biology, National Institute for Medical Research, Mill Hill, London NW7 1AA, U.K.

³ Current address: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.

⁴ Address correspondence and reprint requests to Dr. Nancy Hogg, Cancer Reseach United Kingdom, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3PX, United Kingdom. E-mail address: nancy.hogg{at}cancer.org.uk

⁵ Abbreviations used in this paper: TRIF, Toll/IL-1R domain–containing adaptor-inducing IFN-β; IRF, IFN-regulated factor; poly(I:C), polyinosine-polycytidylic acid; WT, wild type.

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