Targeting Itga8 Mitigates Neurogenic Bladder Fibrosis Driven by Trem2⁺ Macrophage-Derived Fn1 via FAK/RhoA/ROCK Signaling.

Neurogenic bladder (NB)-induced fibrosis is the major cause of irreversible bladder dysfunction, yet the underlying mechanisms remain undefined. Here, leveraging single-cell RNA sequencing, the fibrotic landscape of NB is delineated and a distinct integrin α8 (Itga8) ⁺ fibroblast population. The Itga8⁺ fibroblasts expand substantially during the acute phase post-injury and exhibit a fibrogenic transcriptional profile. Mechanistically, Itga8 is found to coordinate cytoskeletal remodeling via the FAK/RhoA/ROCK signaling to facilitate fibroblast activation. Moreover, fibroblast activation is orchestrated by Trem2⁺ macrophages, which secrete Fn1 to engage Itga8 on fibroblasts, thereby reinforcing the pro-fibrotic communication between fibroblasts and macrophages. Notably, macrophage depletion markedly attenuates fibrosis and restores bladder function, underscoring their pivotal role in NB pathogenesis. In vivo, conditional deletion of Itga8 (Col1a2-CreERT; Itga8