Myeloperoxidase: A new player in autoimmunity

Abstract

Myeloperoxidase (MPO) is the most toxic enzyme found in the azurophilic granules of neutrophils. MPO utilizes H₂O₂ to generate hypochlorous acid (HClO) and other reactive moieties, which kill pathogens during infections. In contrast, in the setting of sterile inflammation, MPO and MPO-derived oxidants are thought to be pathogenic, promoting inflammation and causing tissue damage. In contrast, evidence also exists that MPO can limit the extent of immune responses. Elevated MPO levels and activity are observed in a number of autoimmune diseases including in the central nervous system (CNS) of multiple sclerosis (MS) and the joints of rheumatoid arthritis (RA) patients. A pathogenic role for MPO in driving autoimmune inflammation was demonstrated using mouse models. Mechanisms whereby MPO is thought to contribute to disease pathogenesis include tuning of adaptive immune responses and/or the induction of vascular permeability.

Keywords: Autoimmunity; Multiple sclerosis; Myeloperoxidase; Neutrophil; Oxidative stress; Rheumatoid arthritis.

Fig. 1

The influence of MPO on the immune responses. The immune response induced by subcutaneous injection of OVA/LPS or OVA/CFA, leads to recruitment of neutrophils to the local lymph node where they are activated releasing NETs and MPO. MPO released from neutrophils limits the activation of DC as measured by CD86 expression and reduced IL-12 production. Consequently, T cell proliferation and proinflammatory cytokine production is reduced. Consistent with this, MPO-deficient mice have enhanced antigen induced arthritis (AIA). However, the reduced disease severity in MPO-deficient mice in the K/BxN arthritis and collagen induced arthritis (CIA) mouse models, indicates that MPO can also be pathogenic in disease.

Fig. 2

MPO and the vasculature. Leukocyte transmigration across the endothelium is supported by electrostatic interactions between positively charged MPO and the cell membrane containing charged heparin-sulfate proteoglycans (HSPG). Additionally, MPO generates HClO that increases endothelial permeability. Released MPO is transcytosed and deposited in the vascular extracellular matrix (ECM). In the ECM, MPO utilizes NO, leading to impaired vascular relaxation and the generation of NO₂⁻, which modifies the ECM component fibronectin.