title: Loss of TLR2 worsens spontaneous colitis in MDR1A deficiency through commensally induced pyroptosis.
abstract: Variants of the multidrug resistance gene (MDR1/ABCB1) have been associated with increased susceptibility to severe ulcerative colitis (UC). In this study, we investigated the role of TLR/IL-1R signaling pathways including the common adaptor MyD88 in the pathogenesis of chronic colonic inflammation in MDR1A deficiency. Double- or triple-null mice lacking TLR2, MD-2, MyD88, and MDR1A were generated in the FVB/N background. Deletion of TLR2 in MDR1A deficiency resulted in fulminant pancolitis with early expansion of CD11b(+) myeloid cells and rapid shift toward TH1-dominant immune responses in the lamina propria. Colitis exacerbation in TLR2/MDR1A double-knockout mice required the unaltered commensal microbiota and the LPS coreceptor MD-2. Blockade of IL-1β activity by treatment with IL-1R antagonist (IL-1Ra; Anakinra) inhibited colitis acceleration in TLR2/MDR1A double deficiency; intestinal CD11b(+)Ly6C(+)-derived IL-1β production and inflammation entirely depended on MyD88. TLR2/MDR1A double-knockout CD11b(+) myeloid cells expressed MD-2/TLR4 and hyperresponded to nonpathogenic Escherichia coli or LPS with reactive oxygen species production and caspase-1 activation, leading to excessive cell death and release of proinflammatory IL-1β, consistent with pyroptosis. Inhibition of reactive oxygen species-mediated lysosome degradation suppressed LPS hyperresponsiveness. Finally, active UC in patients carrying the TLR2-R753Q and MDR1-C3435T polymorphisms was associated with increased nuclear expression of caspase-1 protein and cell death in areas of acute inflammation, compared with active UC patients without these variants. In conclusion, we show that the combined defect of two UC susceptibility genes, MDR1A and TLR2, sets the stage for spontaneous and uncontrolled colitis progression through MD-2 and IL-1R signaling via MyD88, and we identify commensally induced pyroptosis as a potential innate immune effector in severe UC pathogenesis.
authors: Division of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors: Birgit
authors: B
authors: Ey
authors: Annette
authors: A
authors: Eyking
authors: Magdalena
authors: M
authors: Klepak
authors: Nita H
authors: NH
authors: Salzman
authors: Joachim R
authors: JR
authors: Göthert
authors: Michael
authors: M
authors: Rünzi
authors: Kurt W
authors: KW
authors: Schmid
authors: Guido
authors: G
authors: Gerken
authors: Daniel K
authors: DK
authors: Podolsky
authors: Elke
authors: E
authors: Cario
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D017353:Gene Deletion; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D039481:CD11b Antigen; D053583:Interleukin-1beta; D051218:Lymphocyte Antigen 96; D053594:Myeloid Differentiation Factor 88; D017382:Reactive Oxygen Species; D051195:Toll-Like Receptor 2; C095122:multidrug resistance protein 3; D020170:Caspase 1
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