Fas (CD95) induces macrophage proinflammatory chemokine production via a MyD88-dependent, caspase-independent pathway.
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.
Altemeier
William A
WA
Department of Medicine, University of Washington School of Medicine, 1959 NE Pacific St., Seattle, WA 98105-6522, USA. billa@u.washington.edu
Zhu
Xiaodong
X
Berrington
William R
WR
Harlan
John M
JM
Liles
W Conrad
WC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology*; D020169:Caspases / Q000378:metabolism*; D054360:Chemokine CXCL1; D018925:Chemokines / Q000494:pharmacology; D019743:Chemokines, CXC / Q000378:metabolism*; D005260:Female; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology; D015398:Signal Transduction; D014764:Viral Proteins / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; D015843:Serpins; D014764:Viral Proteins; D019014:fas Receptor; C074641:interleukin-1beta-converting enzyme inhibitor; D020169:Caspases