TY - JOUR
T1 - Cutting edge
T2 - Endoplasmic reticulum stress licenses macrophages to produce mature IL-1b in response to TLR4 stimulation through a caspase-8- and trif-dependent pathway
AU - Shenderov, Kevin
AU - Riteau, Nicolas
AU - Yip, Ronald
AU - Mayer-Barber, Katrin D.
AU - Oland, Sandy
AU - Hieny, Sara
AU - Fitzgerald, Pat
AU - Oberst, Andrew
AU - Dillon, Christopher P.
AU - Green, Douglas R.
AU - Cerundolo, Vincenzo
AU - Sher, Alan
PY - 2014/3/1
Y1 - 2014/3/1
N2 - The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1b. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro- IL-1b in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1b occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1b is fully dependent on caspase-8. Intriguingly, we found that neither the unfolded protein response transcription factors XBP1 and CHOP nor the TLR4 adaptor molecule MyD88 is necessary for caspase-8 activation. Instead, both caspase activation and IL-1b production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1-driven tissue pathology in certain disease settings.
AB - The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1b. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro- IL-1b in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1b occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1b is fully dependent on caspase-8. Intriguingly, we found that neither the unfolded protein response transcription factors XBP1 and CHOP nor the TLR4 adaptor molecule MyD88 is necessary for caspase-8 activation. Instead, both caspase activation and IL-1b production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1-driven tissue pathology in certain disease settings.
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U2 - 10.4049/jimmunol.1302549
DO - 10.4049/jimmunol.1302549
M3 - Review article
C2 - 24489101
AN - SCOPUS:84896500701
SN - 0022-1767
VL - 192
SP - 2029
EP - 2033
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -