Abstract
Dying cells stimulate inflammation, and this response is thought to contribute to the pathogenesis of many diseases. Very little has been known, however, about how cell death triggers inflammation. We found here that the acute neutrophilic inflammatory response to cell injury requires the signaling protein myeloid differentiation primary response gene 88 (Myd88). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor 2 (Tlr2) and Tlr4 and normal responses in mice lacking Tlr1, Tlr3, Tlr6, Tlr7, Tlr9, Tlr11 or the interleukin-18 receptor (IL-18R). However, mice lacking IL-1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL-1α, and IL-1R function was required on non–bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL-1R–Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggest that inhibiting the IL-1R–Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.
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Acknowledgements
The authors thank R. Schreiber (Washington University) for the generous gift of IL-1α, IL-1β, IL-1R and glutathione S-transferase (isotype control) antibodies, R. Flavell (Yale University) for the caspase 1–deficient mice, M. Bianchi (San Raffaele Scientific Institute) for Hmgb1+/+ and Hmgb1−/− fibroblast cells, and K. Dresser and T. Smith (University of Massachusetts Medical School) for help with histology and photomicrographs. H.K. was supported in part by funds from Kanae Foundation. C.J.C. was supported in part by National Science Council, Taiwan (NSC95-2313-B002-120). This work was supported by grants from the US National Institutes of Health to K.L.R., and core resources supported by the Diabetes Endocrinology Research Center grant DK32520 were also used.
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C.J.C. and H.K. performed the experiments and contributed to the writing of the manuscript. D.G. provided reagents and advice and contributed conceptually to the project. G.R. performed statistical analyses. S.A. provided mice. K.L.R. initiated and supervised the project and contributed to the writing of the manuscript.
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Supplementary Fig. 1
Injured cell-induced inflammation in C57BL/6 and B6129 (PDF 61 kb)
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Chen, CJ., Kono, H., Golenbock, D. et al. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 13, 851–856 (2007). https://doi.org/10.1038/nm1603
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DOI: https://doi.org/10.1038/nm1603
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