Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1β in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway.
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-1β. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro-IL-1β in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1β occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1β 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-1β production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1-driven tissue pathology in certain disease settings.
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK, OX3 9DS.|Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. 20892.
Kevin
K
Shenderov
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. 20892.
Nicolas
N
Riteau
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK, OX3 9DS.
Ronald
R
Yip
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. 20892.
Katrin D
KD
Mayer-Barber
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. 20892.
Sandy
S
Oland
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. 20892.
Sara
S
Hieny
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Pat
P
Fitzgerald
Department of Immunology, University of Washington, Seattle, WA 98109.
Andrew
A
Oberst
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Christopher P
CP
Dillon
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Douglas R
DR
Green
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK, OX3 9DS.
Vincenzo
V
Cerundolo
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. 20892.
Alan
A
Sher
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D000071701:Regulatory Factor X Transcription Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D056811:Unfolded Protein Response / Q000502:physiology; D000071717:X-Box Binding Protein 1
D033942:Adaptor Proteins, Vesicular Transport; D053181:Caspase 8; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D000071701:Regulatory Factor X Transcription Factors; D051197:Toll-Like Receptor 4; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C497250:Ddit3 protein, mouse; C587672:IL1B protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C000605544:Xbp1 protein, mouse; C505526:Casp8 protein, mouse