TLR1 deficiency associates with immune dysregulation and colitis.

Toll-like receptor 1 (TLR1), a member of the TLR family, assumes a pivotal role in pathogen recognition and the activation of innate immunity. In this study, we have identified a homozygous truncating TLR1 variant associated with immune dysregulation and colitis. Peripheral blood mononuclear cells derived from the patient manifested robust inflammatory signatures and defective TLR1 signaling responses. TLR1-deficient cells demonstrated impaired production of a wide-spectrum of inflammatory cytokines, antimicrobial peptides, and the anti-inflammatory cytokine IL-10 following stimulation with TLR1 ligand. This defect culminated in impaired bactericidal activity and dysregulated termination of the inflammatory response, especially characterized by a significant enhancement of the CXCR3 signaling pathway. TLR1-KO mice exhibited increased susceptibility to Salmonella Typhimurium infection and dextran sulfate sodium-induced colitis, with augmented infiltration of monocytes and macrophages in the pathological colon. The administration of IL-10 significantly alleviated the colitis phenotype associated with TLR1 deficiency in mice. This investigation underscores the crucial function of TLR1 in orchestrating a context-appropriate immune response to microbial invasion while averting excessive inflammation, thereby highlighting its indispensable role in human physiology and disease.