Identification of a key pathway required for the sterile inflammatory response triggered by dying cells.
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-1alpha, 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.
Chen
Chun-Jen
CJ
Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Room S2-109, Worcester, Massachusetts 01655, USA.
Kono
Hajime
H
Golenbock
Douglas
D
Reed
George
G
Akira
Shizuo
S
Rock
Kenneth L
KL
D000818:Animals; D016923:Cell Death; D002460:Cell Line; D017353:Gene Deletion; D007249:Inflammation / Q000378:metabolism*; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides; D009195:Peroxidase / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D053582:Interleukin-1alpha; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; C029579:antiarrhythmic peptide; D009195:Peroxidase