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TLR 4 acts as a death receptor for ultraviolet radiation ( UVR ) through IRAK ‐independent and FADD ‐dependent pathway in macrophages
Author(s) -
Zhou Hua,
Harberts Erin,
Fishelevich Rita,
Gaspari Anthony A.
Publication year - 2016
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.13222
Subject(s) - fadd , apoptosis , death domain , tradd , lipopolysaccharide , biology , caspase 8 , programmed cell death , microbiology and biotechnology , receptor , chemistry , caspase , immunology , biochemistry
UVR ‐induced apoptosis in cutaneous antigen presenting cells ( APC ) causes systemic immune suppression and is dependent on TLR 4/MyD88 signalling, but the apoptotic signalling pathways have not been defined. Macrophages pretreated with lipopolysaccharide ( LPS ) were unresponsive to subsequent LPS treatment, however, but were susceptible to UVR ‐induced apoptosis. Macrophage survival and apoptotic events after UVR were also unaffected by treatment with TLR 4 antagonists, a blocking IgG or a TLR 4 analog antagonist, suggesting that UVR cell death is independent of a soluble ligand. After UVR , IRAK 4 KDKI (catalytically inactive IRAK 4) and wild‐type ( WT ) macrophages show equivalent levels of survival, as measured by MTT assay, and apoptosis, as measured by cleaved caspase‐3. Furthermore, in macrophages from both mice, UVR activated caspase‐8 and PARP , while inactivating Rip3. This finding is supported by a lack of IRAK 1 degradation after UVR , compared to treatment with TLR 2 or TLR 4 agonists. UVR induced association of MyD88 with FADD , an extrinsic apoptotic pathway protein, but not IRAK 4. UVR ‐induced migration of FADD to the cell membrane of WT macrophages, but not MyD88 −/− macrophages, was observed (confocal microscopy). Co‐immunoprecipitation using an epitope‐tagged MyD88 revealed that FADD , but not TRADD , was recruited to MyD88 within 30 minutes of UVR exposure. UVR engages TLR 4/MyD88 as a death signalling complex, rather than the classical inflammatory signalling pathway triggered by PAMP recognition of TLR 4. These studies provide the rationale for the future development of topical TLR 4 modulating therapies to interfere with this UVB ‐mediated apoptosis and the associated negative consequences of immune suppression.