Neutrophil CD11b is a pivotal PANoptosis marker correlated with disease activity in antineutrophil cytoplasmic antibody-associated vasculitis

Neutrophil-mediated inflammation plays a crucial role in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Dysregulated neutrophil death has been implicated in promoting neutrophil priming and activation. PANoptosis, an inflammatory programmed cell death, participates in the development of various autoimmune diseases. The current study aims to identify the key PANoptosis-related marker and investigate its association with disease activity of AAV. Gene microarray data of patients with ANCA-associated glomerulonephritis (ANCA-GN) was downloaded from the Gene Expression Omnibus (GEO). PANoptosis-associated genes were sourced from GeneCards. The hub-marker of PANoptosis-related genes was identified by integrated bioinformatical analysis. The single-cell sequencing data from ANCA-GN mice were used to determine the location of hub genes. Then levels of activated CD11b on neutrophils from peripheral blood, as well as soluble CD11b in urine and plasma were measured in AAV patients. Their associations with clinicopathological parameters of AAV patients were subsequently analyzed. Co-localization of CD11b and neutrophils in renal specimens of AAV patients was evaluated by immunofluorescence staining. Changes of intracellular metabolic pathways of neutrophils from AAV patients were further investigated. A small molecule inhibitor was used to explore the effect of intracellular fatty acid metabolism (FAO) on neutrophil CD11b activation and PANoptosis. CD11B was identified as the pivotal PANoptosis-related gene in AAV by integrated bioinformatics analysis. The level of activated CD11b on neutrophils was significantly higher in active AAV patients compared with healthy controls, and elevated neutrophil CD11b levels positively correlated with disease activity, as evidenced by higher levels of hypersensitive C-reactive protein (hCRP), increased Birmingham Vasculitis Activity Score (BVAS), elevated serum creatinine levels at sampling and a higher proportion of cellular crescents in renal specimens of AAV patients. We also demonstrated the presence of neutrophil CD11b in renal specimen of AAV patients. Moreover, along with elevated Cd11b expression, neutrophils from ANCA-GN mice exhibited an aberrant FAO phenotype and a down-regulated peroxisome proliferators-activated receptor (PPAR)-α pathway, as compared with healthy controls. GW7647, a PPARα agonist, could alleviate AAV serum-induced neutrophil CD11b activation and PANoptosis. CD11B was a pivotal PANoptosis-related gene in AAV. The level of activated CD11b on neutrophils was associated with disease activity in AAV patients.