title: Posttranscriptional control of NLRP3 inflammasome activation in colonic macrophages.
abstract: Colonic macrophages (cMPs) are important for intestinal homeostasis as they kill microbes and yet produce regulatory cytokines. Activity of the NLRP3 (nucleotide-binding leucine-rich repeat-containing pyrin receptor 3) inflammasome, a major sensor of stress and microorganisms that results in pro-inflammatory cytokine production and cell death, must be tightly controlled in the intestine. We demonstrate that resident cMPs are hyporesponsive to NLRP3 inflammasome activation owing to a remarkable level of posttranscriptional control of NLRP3 and pro-interleukin-1β (proIL-1β) protein expression, which was also seen for tumor necrosis factor-α and IL-6, but lost during experimental colitis. Resident cMPs rapidly degraded NLRP3 and proIL-1β proteins by the ubiquitin/proteasome system. Finally, blocking IL-10R-signaling in vivo enhanced NLRP3 and proIL-1β protein but not mRNA levels in resident cMPs, implicating a role for IL-10 in environmental conditioning of cMPs. These data are the first to show dramatic posttranscriptional control of inflammatory cytokine production by a relevant tissue-derived macrophage population and proteasomal degradation of proIL-1β and NLRP3 as a mechanism to control inflammasome activation, findings which have broad implications for our understanding of intestinal and systemic inflammatory diseases.
authors.affiliation: Mucosal Immunobiology Section, Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Filardy
authors.affiliation: Mucosal Immunobiology Section, Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: Cellular Biology and Viral Immunology Sections, Laboratory of Viral Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bennink
authors.affiliation: Cellular Biology and Viral Immunology Sections, Laboratory of Viral Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yewdell
authors.affiliation: Mucosal Immunobiology Section, Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Kelsall
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D058847:Inflammasomes / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D053701:Receptors, Interleukin-10 / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053701:Receptors, Interleukin-10; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D046988:Proteasome Endopeptidase Complex