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Loss of TLR2 worsens spontaneous colitis in MDR1A deficiency through commensally induced pyroptosis
Birgit Ey1, Annette Eyking, Magdalena Klepak
1Division of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
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.
Insights
Genetic defects in multidrug resistance (MDR1) and Toll-like receptor 2 (TLR2) genes promote severe ulcerative colitis (UC). Commensal bacteria trigger pyroptosis via MyD88 and IL-1R signaling, driving inflammation in UC.
Area of Science:
- Immunology
- Gastroenterology
- Genetics
Background:
- Variants of the multidrug resistance gene (MDR1/ABCB1) are linked to increased ulcerative colitis (UC) susceptibility.
- Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) signaling pathways, including MyD88, are implicated in chronic inflammation.
Purpose of the Study:
- To investigate the role of TLR/IL-1R signaling and MyD88 in the pathogenesis of colonic inflammation in MDR1A-deficient mice.
- To explore the link between specific gene variants (TLR2, MDR1) and UC severity in patients.
Main Methods:
- Generation of double- or triple-null mice lacking TLR2, MD-2, MyD88, and MDR1A.
- Analysis of immune responses, including myeloid cell expansion and T-helper cell profiles.
- Assessment of IL-1β production, reactive oxygen species, caspase-1 activation, and pyroptosis.
- Comparison of caspase-1 expression and cell death in UC patients with and without specific gene variants.
Main Results:
- Deletion of TLR2 in MDR1A-deficient mice led to fulminant pancolitis, characterized by myeloid cell expansion and TH1 responses.
- Colitis exacerbation required intact commensal microbiota and the LPS coreceptor MD-2.
- IL-1β production and inflammation were dependent on MyD88 and IL-1R signaling.
- TLR2/MDR1A-deficient myeloid cells exhibited hyperresponsiveness to LPS, leading to pyroptosis and excessive IL-1β release.
- UC patients with TLR2-R753Q and MDR1-C3435T polymorphisms showed increased caspase-1 expression and cell death.
Conclusions:
- Combined defects in MDR1A and TLR2 facilitate spontaneous colitis progression via MD-2/IL-1R/MyD88 signaling.
- Commensally induced pyroptosis is identified as a key innate immune mechanism in severe UC pathogenesis.
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