Neutrophil-Driven Inflammation in Pediatric Chronic Recurrent Multifocal Osteomyelitis.

Abstract

Objective: Chronic recurrent multifocal osteomyelitis (CRMO) is a pediatric autoinflammatory bone disease with poorly defined pathophysiology and limited biomarkers. Murine models implicate neutrophils, neutrophil-derived interleukin-1β, and the adapter protein PSTPIP2, but direct evidence in human CRMO is lacking. This study aims to translate findings from mouse models to human disease by investigating the role of neutrophils and PSTPIP2 in CRMO.

Methods: Blood samples from 34 patients with CRMO and 20 controls were analyzed by flow cytometry, biochemical assays, and transcriptomic profiling of purified neutrophils. Patients were evaluated across treatment groups (untreated or treated with nonsteroidal anti-inflammatory drugs, zoledronate, or anti-tumor necrosis factor [anti-TNF] therapy). Neutrophil activation, PSTPIP2 expression, inflammatory gene responses, and correlations with clinical parameters were assessed.

Results: CRMO neutrophils displayed chronic activation marked by reduced CD62L expression (P = 0.0016; Mann-Whitney test), which correlated with magnetic resonance imaging lesion burden. PSTPIP2 protein levels were consistently decreased (P = 0.0006) despite elevated messenger RNA expression (P = 0.0005) and absence of coding mutations, suggesting inflammation-associated posttranscriptional regulation. Both neutrophil activation and PSTPIP2 down-regulation normalized in patients receiving anti-TNF therapy. Unlike murine models, IL1B expression and CXCL8 expression were not increased. Transcriptomic profiling (four patients and three controls) identified enrichment of NF-κB signaling and inflammatory and chemotaxis pathways with up-regulation of CCL4, CCL4L2, ATL1, VNN1, H2BC7, and LINC02207 and down-regulation of ISL2. Several transcripts correlated with clinical measures of disease burden.

Conclusion: These findings identify neutrophil activation and inflammation-sensitive PSTPIP2 deficiency as central features of human CRMO, suggest chemokines as potential biomarkers, and mechanistically explain why TNF blockade provides clinical benefit.