Macrophage-derived CD38 mediates colitis through NAD+ depletion

Abstract

Colitis, a chronic inflammatory bowel disease (IBD), is pathologically linked to immune dysregulation; however, the contribution of cellular metabolic alterations to its pathogenesis remains incompletely understood. In this study, untargeted metabolomic analysis revealed marked disruption of NAD⁺ metabolism, accompanied by increased expression of CD38, a major NAD⁺-glycohydrolase, in colitis. Restoring NAD⁺ levels through supplementation with its precursors or pharmacological inhibition of CD38 activity effectively alleviated the pathological symptoms of colitis. Mechanistically, colitis induced a pronounced upregulation of CD38 specifically in macrophages. Myeloid-specific deletion of Cd38 significantly attenuated both metabolic disturbances and inflammatory responses associated with colitis. These findings identify macrophage CD38 as a critical regulator of intestinal inflammation and highlight the CD38/NAD⁺ axis as a potential therapeutic target for IBD.

Key points

• Altered NAD⁺ metabolism is closely associated with intestinal inflammation, yet the specific cellular mechanisms contributing to this decline remain to be fully elucidated.
• By supplementing with nicotinamide mononucleotide or inhibiting the enzyme CD38 that consumes NAD⁺ with drugs, the NAD⁺ level can be effectively restored, which can alleviate the colitis induced by dextran sulphate sodium to a certain extent.
• During intestinal inflammation, the upregulation of CD38 is predominantly driven by infiltrating macrophages.
• Myeloid-specific deletion of CD38 preserves NAD⁺ homeostasis and ameliorates colitis, highlighting its essential role in disease progression.
• Targeting macrophage CD38 establishes a key regulatory link between NAD⁺ metabolism and intestinal inflammation, providing a potential therapeutic strategy for inflammatory bowel diseases.