# Tubule‐Derived IFN‐α Promotes GSDMD‐Mediated Macrophage Pyroptosis to Drive Renal Inflammation and Fibrosis Through JAK2/STAT2 Activation

## TL;DR

This study shows how kidney inflammation and scarring are driven by a feedback loop between injured cells and immune cells, offering a new target for treating chronic kidney disease.

## Contribution

The study identifies a novel STAT2/IRF9-dependent IFN-α signaling pathway linking TEC injury to macrophage pyroptosis in CKD.

## Key findings

- GSDMD is upregulated in kidney macrophages after injury and correlates with fibrosis severity in CKD.
- TEC-derived IFN-α activates the JAK2/STAT2 axis in macrophages, promoting GSDMD expression and pyroptosis.
- Blocking IFN-α reduces pyroptosis, inflammation, and fibrosis in mouse models of CKD.

## Abstract

Macrophages exhibit high plasticity in response to tubular epithelial cell (TEC) injury. Gasdermin D (GSDMD)‐mediated pyroptosis amplifies the inflammatory and fibrogenic cascade, yet its role in chronic kidney disease (CKD) remains elusive. Herein, GSDMD is upregulated in kidney macrophages following unilateral renal ischemia‐reperfusion injury (UIRI) or folic acid‐induced injury, paralleling elevated pyroptosis rates. Clinically, the active fragment GSDMD‐N localizes primarily to CD68⁺ macrophages, and its renal level positively correlates with fibrosis severity across diverse CKD etiologies, reinforcing its pathogenic relevance. Macrophage‐specific deletion of Gsdmd ameliorates pyroptosis, inflammation, and renal fibrosis in both murine models, without affecting acute tubular damage in bilateral IRI. Mechanistically, injured TECs initiate this cascade through secreted IFN‐α, which activates the IFNAR1/JAK2/STAT2 axis in macrophages​. STAT2 then forms a complex with IRF9, directly binding to the Gsdmd promoter to transcriptionally upregulate GSDMD expression. Genetic ablation of Jak2, Stat2, or Ifnar1 reduces GSDMD and GSDMD‐N levels and inhibits IL‐1β/IL‐18 secretion. Notably, administration of an IFN‐α neutralizing antibody attenuates UIRI‐induced pyroptotic macrophage, inflammation, and renal fibrosis. Collectively, the findings uncover a STAT2/IRF9‐dependent paracrine IFN‐α feedback loop that orchestrates GSDMD‐mediated pyroptosis, linking injured TECs to macrophage‐driven renal inflammation and fibrosis. Targeting this axis represents a promising strategy to halt CKD progression.

Mao and colleagues uncover a STAT2/IRF9‐dependent signaling axis through which tubular epithelial cell (TEC)‐derived IFN‐α induces gasdermin D (GSDMD)‐mediated pyroptosis in macrophages. This TEC‐macrophage feedback loop amplifies renal inflammation and fibrosis, providing mechanistic insight into the progression of chronic kidney disease and revealing a potential direction for therapeutic intervention.