Comparative analysis of myeloperoxidase deficiency in humans and mice: Conserved and species-specific effects on neutrophil biology.

BACKGROUND

Myeloperoxidase (MPO), a heme-containing enzyme released by activated polymorphonuclear neutrophils (PMNs) represents a key mediator of inflammation-driven cardiovascular disease, positioning MPO as a promising therapeutic target. However, substantial interspecies differences between murine and human neutrophil biology challenge the translation of preclinical findings from rodent studies into patients.

METHODS

11,608 patients were screened for MPO deficiency using the ADVIA 2120i system. 282 individuals exhibited a reduced MPO activity. 56 patients were eligible, consented to be enrolled and were compared to 20 control patients. MPO levels and activity were measured by enzyme-linked immunosorbent assay (ELISA), immunoblotting, a tetramethylbenzidin (TMB)-based peroxidase and nitric oxide (NO)-consumption assay. For cross-species analysis, shotgun proteomics, Gene Ontology (GO) and REACTOME pathway enrichment analyses were conducted on bone marrow derived PMNs from Mpo-/- mice and human MPO-deficient PMNs.

RESULTS

Patients with persistent (MPOlow, n = 12) and transient (MPOrec, n = 44) MPO deficiency were identified. MPOlow individuals showed significantly decreased neutrophil MPO concentrations, enzymatic activity, and plasma MPO levels. Proteomic profiling revealed substantial overlap in altered biological processes across both species. Species-specific enrichments included humoral immunity, complement activation, and coagulation in humans, phagocytosis, chemotaxis, and transcriptional regulation in mice. These differences have been reported alongside distinct signaling patterns, with predominance of Mitogen-activated protein (MAP)-kinase and cytokine activity in humans, and Ras homolog family (Rho)-GTPase pathways in mice.

CONCLUSION

MPO deficiency leads to broadly conserved alterations in neutrophil immune and stress responses across humans and mice. However, similar functional outcomes may involve different signaling pathways in each species contributing to divergent phenotypes in disease models. These findings underscore species-specific mechanisms in MPO-related neutrophil biology and highlight critical considerations for translating MPO-targeted therapies from animal models to human disease.