Interaction between NKG2D and its ligands MICA/B activates the DAP12/SYK/p53/p21 axis to drive pulmonary fibrosis

Pulmonary fibrosis (PF) is a progressive, fatal interstitial lung disease with limited therapeutic options. Emerging evidence implicates immune-fibrotic crosstalk in PF pathogenesis, although the underlying molecular mechanisms remain poorly defined. While Natural Killer (NK) cells and their activating receptor NKG2D have been linked to fibrotic processes, their functional role in PF is unclear. This study investigates the NKG2D-DAP12-SYK-p53-p21 signaling axis as a potential driver of PF through immune-fibroblast interactions.

We characterized the dynamic expression profile of NKG2D in pulmonary tissues derived from bleomycin (BLM)-induced model mice. Mechanistic investigations utilized AAV5-mediated NKG2D overexpression systems, coimmunoprecipitation assays, and functional pathway dissection to elucidate the DAP12-SYK-p53-p21 signaling axis. Therapeutic efficacy was evaluated via anti-NKG2D antibody treatment in murine PF models via histopathology, micro-CT imaging, and molecular profiling of fibrosis markers (collagen-I, fibronectin) and senescence-associated proteins (p-p53, p21).

Significant upregulation of NKG2D on pulmonary NK cells and its ligands on fibroblasts was detected in murine PF. AAV5-mediated NKG2D overexpression exacerbated BLM induced fibrosis, as evidenced by increased fibrosis scores alongside elevated levels of collagen-I and fibronectin. Mechanistically, NKG2D activation triggered DAP12-dependent SYK activation, leading to p53 phosphorylation and p21-mediated cellular senescence. Treatment with anti-NKG2D antibodies effectively mitigated disease progression by reducing collagen deposition while suppressing the downstream expression of SYK and p21.

This study proposes that the NKG2D-DAP12-SYK-p53-p21 axis may represent a novel pathogenic pathway in PF, potentially linking immune dysregulation to cellular senescence. Therapeutic targeting of NKG2D could thus hold promise for the concurrent modulation of immune-fibrotic crosstalk and fibrotic progression, which might offer a new strategic direction for PF management.