Macrophage-neutrophil crosstalk via the Selplg-Sell-YAP axis drives NETosis and MASH-associated liver fibrosis

Metabolic dysfunction-associated steatohepatitis (MASH)-associated fibrosis is a pivotal stage toward end-stage liver disease. However, the immune mechanisms orchestrating the transition from inflammation to fibrosis remain elusive. We aimed to dissect the myeloid-cell crosstalk driving this transition and identify therapeutic targets.

Single-cell transcriptomic analysis of MASH mouse livers revealed expansion of infiltrating Selplg + macrophages and enhanced macrophage-neutrophil communication through the Selplg-Sell axis. This axis was consistently activated in CDAHFD- and WD+CCl 4 -induced MASH fibrosis models, and its cellular components were spatially enriched and associated with fibrosis severity in human MASLD liver tissues. Structural modeling showed that macrophage-derived Selplg engaged neutrophil Sell through a glycan-dependent interface involving sialyl-Lewis X (sLeX) recognition. In primary cell co-culture systems, Selplg-Sell engagement required direct cell-cell contact and activated neutrophil p38-MST1/2-YAP signaling, leading to YAP-dependent transcriptional activation of neutrophil extracellular trap (NET) effector programs. NETs subsequently acted as extracellular scaffolds that promoted integrin-dependent activation of latent TGF-β1, thereby driving hepatic stellate cell activation. Pharmacological blockade with the sLeX mimetic TBC-1269 or YAP inhibition attenuated hepatic inflammation, NET burden, and fibrosis under both preventive and therapeutic settings. Macrophage-lineage-specific Selplg deficiency further recapitulated these protective effects, confirming macrophage-derived Selplg as an upstream driver of this pathogenic circuit.

This study defines a macrophage-neutrophil-HSC signaling axis linking metabolic inflammation to fibrotic remodeling in MASH. Macrophage-derived Selplg drives Sell-dependent YAP-mediated NETosis, while NETs further promote latent TGF-β1 activation and HSC activation. These findings support the axis as a therapeutic target for MASH-associated liver fibrosis.