Fas (CD95) induces macrophage proinflammatory chemokine production via a MyD88-dependent, caspase-independent pathway

WA Altemeier, X Zhu, WR Berrington… - Journal of Leucocyte …, 2007 - academic.oup.com
Journal of Leucocyte Biology, 2007academic.oup.com
Activation of the prototypical death receptor, Fas (CD95), can induce both caspase-
dependent cell death and production of proinflammatory chemokines, leading to neutrophil
recruitment and end-organ injury. The precise mechanism (s) by which Fas up-regulates
chemokine production and release, is currently unclear. We hypothesized that Fas-induced
chemokine release by macrophages is dependent on the MyD88 adaptor molecule and
independent of caspase activity. To test this hypothesis, we measured chemokine response …
Abstract
Activation of the prototypical death receptor, Fas (CD95), can induce both caspase-dependent cell death and production of proinflammatory chemokines, leading to neutrophil recruitment and end-organ injury. The precise mechanism(s) by which Fas up-regulates chemokine production and release, is currently unclear. We hypothesized that Fas-induced chemokine release by macrophages is dependent on the MyD88 adaptor molecule and independent of caspase activity. To test this hypothesis, we measured chemokine response to Fas activation both in RAW 264.7 cells with RNAi-attenuated MyD88 expression and in MyD88-deficient primary macrophages. We found that Fas-induced chemokine release was abrogated in the absence of MyD88. In vivo, MyD88−/− mice had impaired CXCL1/KC release and polymorphonuclear cell recruitment in response to intratracheal treatment with the Fas-activating monoclonal antibody, Jo-2. Furthermore, Fas-induced chemokine release was not dependent on either IL-1 receptor signaling or on caspase activity. We conclude that MyD88 plays an integral role in Fas-induced macrophage-mediated inflammation.
Oxford University Press