DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids
Peter F. Flood, Á Fanning, Jerzy A. Woznicki, Tadhg Crowley, Andrea S. Christopher, Alessandra Vaccaro, Aileen Houston, Sheila M. McSweeney, Sarah A. Ross, Aileen Hogan, Elizabeth Brint, Agnieszka Skowyra, Milán Bustamante, Monica Ambrose, Gerard M. Moloney, John MacSharry, Marie‐Louise Hammarström, Margot Hurley, Christine Fitzgibbons, Eamonn M.M. Quigley, Fergus Shanahan, Syed A. Zulquernain, Jane McCarthy, G. Steven Dodson, Karim Dabbagh, Bradford L. McRae, Silvia Melgar, Kenneth Nally
Abstract
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-β, 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.