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. 2012 Dec 15;189(12):5508-12.
doi: 10.4049/jimmunol.1202121. Epub 2012 Nov 9.

Cutting edge: FAS (CD95) mediates noncanonical IL-1β and IL-18 maturation via caspase-8 in an RIP3-independent manner

Lukas Bossaller  1 , Ping-I Chiang, Christian Schmidt-Lauber, Sandhya Ganesan, William J Kaiser, Vijay A K Rathinam, Edward S Mocarski, Deepa Subramanian, Douglas R Green, Neal Silverman, Katherine A Fitzgerald, Ann Marshak-Rothstein, Eicke Latz
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Cutting edge: FAS (CD95) mediates noncanonical IL-1β and IL-18 maturation via caspase-8 in an RIP3-independent manner

Lukas Bossaller et al. J Immunol. .

Abstract (V体育安卓版)

Fas, a TNF family receptor, is activated by the membrane protein Fas ligand expressed on various immune cells. Fas signaling triggers apoptosis and induces inflammatory cytokine production. Among the Fas-induced cytokines, the IL-1β family cytokines require proteolysis to gain biological activity. Inflammasomes, which respond to pathogens and danger signals, cleave IL-1β cytokines via caspase-1. However, the mechanisms by which Fas regulates IL-1β activation remain unresolved VSports手机版. In this article, we demonstrate that macrophages exposed to TLR ligands upregulate Fas, which renders them responsive to receptor engagement by Fas ligand. Fas signaling activates caspase-8 in macrophages and dendritic cells, leading to the maturation of IL-1β and IL-18 independently of inflammasomes or RIP3. Hence, Fas controls a novel noncanonical IL-1β activation pathway in myeloid cells, which could play an essential role in inflammatory processes, tumor surveillance, and control of infectious diseases. .

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Figures

FIGURE 1
FIGURE 1. IL-1β activation by FAS is dependent on FAS receptor upregulation secondary to TLR priming in BMDMs
A, IL-1β ELISA of SN from BMDMs primed with LPS and stimulated for indicated times with Neo control or mFASL vesicles B, Histogram depicting the MFI of FAS on live-gated BMDM after 24h stimulation with 300 ng/ml CLO97 (line) or 20 ng/ml LPS (line) and untreated controls (tinted). C, IL-1β ELISA of SN from Neo or mFASL stimulated BMDMs, which were left untreated or primed for 24h with LPS or CLO97. D, Histograms of TOPRO-3 stained BMDMs in medium only (left), after addition of mFASL without priming (middle) or after 24h priming with LPS and stimulated with mFASL for 6h (right).
FIGURE 2
FIGURE 2. Inflammasome and caspase-1/11 independent IL-1β processing in BMDMs stimulated with mFASL
A, ELISA for IL-1β of SN from LPS-primed (24h) BMDMs from wt (white bars), ASC-/- (black bars) or Caspase-1/11-/- (grey bars) mice stimulated as indicated for an additional 6h with decreasing concentrations of mFAS-L, Neo or dAdT. B, Immunoblot of SN and cell lysates (CL) of wt and ASC-/- BMDMs of the same assay conditions as in A.
FIGURE 3
FIGURE 3. FAS-induced IL-1β and IL-18 processing is caspase-8 dependent and RIP3 independent
A, Caspase-8 activity in CL from wt, Caspase-8-/-/Rip3-/- or RIP3-/- BMDMs stimulated for 6h with decreasing concentrations of mFAS-L. B-F, Immunoblot (B,F) or ELISA for IL-1β (C,E) and IL-18 (D) of SN from wt, Caspase-8-/-/Rip3-/- or RIP3-/- BMDMs stimulated as indicated.
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