Disturbed LTB4 Metabolism in ILC2s Aggravates Ulcerative Colitis via Intercellular ATP Accumulation

Ulcerative colitis (UC), an inflammatory bowel disease of unknown etiology, has mucosal healing as its primary therapeutic goal. Innate lymphoid cells (ILCs) are crucial for orchestrating the balance between intestinal epithelial injury and repair in this process. However, the metabolic reprogramming and underlying mechanisms of ILCs during UC remain incompletely understood. ILC2s play a crucial role in promoting epithelial repair. This is controlled via eicosanoid metabolism, specifically by the synthesis of leukotriene B4 (LTB4). Additionally, the LTB4 synthesis reaction is the most significant reaction involved in ILCs in UC. We establish that ILC2s regulate their mitochondrial function through autocrine secretion of LTB4, which suppresses detrimental excessive ATP production and consequently maintains cellular homeostasis. This study reveals, at the single-cell level, metabolic reprogramming in ILCs and demonstrates that eicosanoid metabolism – one of the most significant metabolic alterations – sustains the anti-inflammatory function of ILC2s, identifying a novel therapeutic target for promoting mucosal repair in colitis. Clinical trial number: not applicable.