NKG2D as a molecular link between epithelial stress and immune activation in Crohn's disease: therapeutic implications.

Crohn's disease (CD) is a chronic inflammatory bowel disorder driven by dysregulated immune responses, epithelial barrier dysfunction, and progressive tissue damage. Despite advances in biologic therapies, treatment resistance and loss of response remain common. The activating receptor NKG2D, expressed on natural killer cells and T cell subsets, recognizes stress-induced ligands (MICA, MICB, ULBP) upregulated on intestinal epithelial cells under inflammatory conditions. In CD, sustained ligand expression promotes NKG2D-dependent cytotoxicity, pro-inflammatory cytokine release (IFN-γ, IL-17), and lymphocyte trafficking into the mucosa, perpetuating a cycle of epithelial injury and chronic inflammation. Preclinical colitis models and clinical trials with anti-NKG2D monoclonal antibodies (e.g., NNC0142-0002) demonstrate reduced disease activity, improved histological outcomes, and induction of remission in moderate-to-severe CD patients. However, challenges remain, including potential impairment of immune surveillance against infections and tumors, patient heterogeneity, and pathway redundancy. Future directions include biomarker-guided patient selection, combination therapies with anti-TNF or anti-integrin agents, and next-generation biologics such as bispecific antibodies. Understanding the cellular and molecular basis of NKG2D signaling in mucosal inflammation positions this receptor as a promising, mechanistically anchored therapeutic target in Crohn's disease.