Low-dose glucocorticoids attenuate crescentic glomerulonephritis by inhibiting the local differentiation of proinflammatory neutrophils.

Glucocorticoids are widely used to treat autoimmune diseases like crescentic glomerulonephritis (cGN), but their immunosuppressive functions are not fully understood. Here, we generated a single immune cell sequencing atlas at different stages of experimental cGN. We identified a proinflammatory neutrophil subset as important for disease progression and as a glucocorticoid target. Such neutrophils produced proinflammatory cytokines known to drive cGN and expressed Siglec-F and decoy tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (dcTRAIL-R1) in mice and SIGLEC8 in humans. Depleting such neutrophils attenuated disease in mice, whereas their adoptive transfer aggravated disease. They differentiated within the inflamed kidney in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by clonally expanded CD4 T helper 17 (T17) cells and persisted locally longer than normal neutrophils. Glucocorticoids decreased intrarenal numbers of T17 cells and down-regulated GM-CSF receptor expression by neutrophils and reduced their cytokine production. Selective genetic reduction of glucocorticoid receptor expression in neutrophils reenabled their in vivo differentiation during glucocorticoid therapy and aggravated cGN. Low glucocorticoid doses were sufficient to prevent intrarenal neutrophil differentiation in mice, if applied repetitively, even without an initial high-dose steroid pulse. Spatial sequencing of kidney biopsies, especially from patients with high disease activity, uncovered similar neutrophils in intrarenal inflammatory niches, and their abundance was lower after repetitive low-dose glucocorticoid application. These findings identify proinflammatory neutrophils as progression drivers in cGN and suggest that low-dose glucocorticoid therapy may be sufficient to suppress them.

PMID: 41091917