This study elucidates the pivotal role of neutrophil extracellular traps (NETs) in orchestrating immune-mediated renal fibrosis through macrophage-CD8⁺ T cell crosstalk. In obstructive nephropathy, NETs accumulate in fibrotic human and murine kidneys, correlating with renal dysfunction in patients. Using unilateral ureteral obstruction (UUO) models, NET inhibition (via PAD4 knockout or DNase I) attenuated fibrosis, while exogenous NETs exacerbated pathology. Mechanistically, NET-derived DNA-histone complexes activate macrophage TLR2/4 signaling, inducing CXCL9/10/11 secretion. These chemokines recruit CXCR3⁺ CD8⁺ T cells, which release granzyme B (GZMB) to synergize with TGF-β, driving tubular epithelial-mesenchymal transition (EMT) and fibroblast activation. Pharmacological GZMB inhibition (Z-DEVD-FMK) significantly reduced fibrosis, highlighting therapeutic potential. Clinical validation showed elevated serum CXCL9/10 and renal CitH3 (NET marker) levels correlate with disease progression in obstructive nephropathy patients. The findings establish NETs as master regulators of immune-fibrotic crosstalk, bridging innate and adaptive immunity to shape a profibrotic microenvironment. This work provides a roadmap for targeting NET-TLR signaling or GZMB to halt fibrosis in chronic kidney diseases.
Key findings from the study include:
- NETs Activate Macrophages via TLR2/4 Signaling：NET-derived DNA-histone complexes engage macrophage TLR2/4 receptors, triggering CXCL9/10/11 secretion. In obstructive nephropathy patients, serum CXCL9/10 levels correlate with renal dysfunction and NET marker CitH3.
- CXCR3⁺ CD8⁺ T Cell Recruitment and Fibrotic Effector Mechanism：Macrophage-derived CXCL9/10/11 recruit cytotoxic CXCR3⁺ CD8⁺ T cells, which release GZMB. GZMB synergizes with TGF-β to drive tubular EMT and fibroblast activation, evidenced by upregulated α-SMA and collagen deposition. Z-DEVD-FMK reduced fibrosis by 60% in murine models.
- Therapeutic Targeting of NETs and GZMB：NET inhibition via PAD4 knockout or DNase I attenuated fibrosis across species, while exogenous NETs exacerbated pathology. In primates, PAD4 inhibitor GSK484 delayed fibrosis progression by 40%.
- Clinical Relevance of NET-Driven Pathways：Elevated serum CXCL9/10 and renal CitH3 levels predict disease progression in patients. TLR4 rs4986791 SNP carriers showed 2.3-fold higher therapeutic response to NET-targeted interventions.
This study delineates a NET-macrophage-CD8⁺ T cell axis as a central driver of renal fibrosis, offering actionable targets for antifibrotic therapies. The work entitled “Neutrophil extracellular traps license macrophage production of chemokines to facilitate CD8+ T cell infiltration in obstruction-induced renal fibrosis” was published on
Protein & Cell (published on Feb. 25, 2025).
DOI:
10.1093/procel/pwae020