DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids.

DNA sensor pathways can initiate inflammasome, cell death, and type I interferon (IFN) signaling in immune-mediated inflammatory diseases (IMIDs), including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC) by analyzing the expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n = 31), inactive UC (n = 31), active UC (n = 33), and a UC single-cell RNA-Seq dataset. The effects of type I IFN (IFN-ß), IFN-γ, and TNF-α on gene expression, cytokine production, and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLR family pyrin domain-containing 3 (NLRP3), caspase, or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1ß/IL-18/CXCL10. The expression of DNA sensor pathway genes-PYHIN family members [absent in melanoma 2 (AIM2), IFI16, myeloid cell nuclear differentiation antigen (MNDA), and pyrin and HIN domain family member 1 (PYHIN1)- as well as Z-DNA-binding protein 1 (ZBP1), cyclic GMP-AMP synthase (cGAS), and DDX41 was increased in active UC and expressed in a cell type-restricted pattern. Inflammasome genes (CASP1, IL1B, and IL18), type I IFN inducers [stimulator of interferon response cGAMP interactor 1 (STING), TBK1, and IRF3), IFNB1, and type I IFN biomarker genes (OAS2, IFIT2, and MX2) were also increased in active UC. Cotreatment of organoids with IFN-ß or IFN-γ in combination with TNFα increased expression of IFI16, ZBP1, CASP1, cGAS, and STING induced cell death and IL-1ß/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.NEW & NOTEWORTHY This study found that patients with active UC have significantly increased colonic gene expression of cytosolic DNA sensor, inflammasome, STING, and type I IFN signaling pathways. The type I IFN, IFN-ß, in combination with TNF-α induced JAK-dependent but NLRP3 and inflammasome-independent inflammatory cell death of colonic organoids. This novel inflammatory cell death phenotype is relevant to UC immunopathology and may partially explain the efficacy of the JAKinibs tofacitinib and upadacitinib in patients with UC.

Physical Activity in Overlap Syndrome of COPD and Obstructive Sleep Apnea: Relationship With Markers of Systemic Inflammation.

STUDY OBJECTIVES: Low physical activity (PA) is associated with poor health outcomes in chronic obstructive pulmonary disease (COPD). Overlap syndrome (OVS), the co-occurrence of COPD and obstructive sleep apnea (OSA), is highly prevalent. Little is known about PA in OVS, and its relationship with markers of systemic inflammation. METHODS: We studied 256 persons with stable COPD, 61 (24%) of whom had OVS, who were well characterized in two previous PA studies. PA was directly assessed with the Omron HJ-720ITC pedometer. C-reactive protein (CRP) and interleukin-6 (IL-6) were assayed from peripheral blood. Linear regression models, adjusting for age and forced expiratory volume in 1 second (FEV1) % predicted, assessed daily step counts and CRP and IL-6 levels in OVS, compared to COPD alone. Linear regression models, adjusting for age, FEV1 % predicted, and coronary artery disease, assessed the relationships between PA and CRP and IL-6 in those with OVS versus those with COPD alone. RESULTS: Compared to COPD alone, persons with OVS walked 672 fewer steps per day (95% CI -1,317 to -28, P = .041). Those with OVS had significantly higher levels of CRP and IL-6 compared to COPD alone. In OVS, each 1,000 fewer steps walked was associated with a 0.875 ng/mL (95% CI 0.767 to 0.997) increase in IL-6, independent of lung function. CONCLUSIONS: Persons with OVS have significantly lower levels of PA and higher levels of inflammatory biomarkers, compared to COPD alone. Lower PA is significantly associated with higher IL-6 levels in OVS.