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

TL;DR

This study identifies a new pathway involving Itga8 and macrophages that causes bladder fibrosis, suggesting Itga8 as a potential treatment target.

Contribution

The study reveals a novel Itga8-centered fibroinflammatory axis and identifies Itga8 as a promising therapeutic target for neurogenic bladder fibrosis.

Findings

Itga8⁺ fibroblasts expand during the acute phase of neurogenic bladder injury and show a fibrogenic profile.

Trem2⁺ macrophages secrete Fn1 to activate Itga8 on fibroblasts via FAK/RhoA/ROCK signaling, promoting fibrosis.

Inhibition or deletion of Itga8 reduces fibrosis and improves bladder function in vivo.

Abstract

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
fl/fl) or local knockdown of Itga8 significantly attenuates collagen deposition and improves voiding efficiency. Collectively, this study reveals a novel Itga8‐centered fibroinflammatory axis and nominates Itga8 as a promising therapeutic target for delaying fibrosis progression and restoring bladder function.

Normal bladders exhibit quiescent fibroblasts/macrophages, whereas neurogenic bladders show acute‐phase Itga8⁺ fibroblast expansion driven by Trem2⁺ macrophage‐secreted Fn1, which activates FAK/RhoA/ROCK signaling, promotes cytoskeletal remodeling, and upregulates pro‐fibrotic genes. Itga8 inhibition blocks these pathways, delays fibrogenesis, and preserves bladder function.

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