Loss of myeloperoxidase aggravates skin and joint inflammation in the mannan-induced psoriatic arthritis mouse model

Abstract

Psoriasis is a systemic inflammatory skin disorder with a prevalence of 2% in adults. Up to 30% of affected individuals further develop psoriatic arthritis (PsA), which is characterized by additional joint inflammation. Myeloperoxidase (MPO) is strongly expressed by neutrophils and, to a lesser extent, also by other myeloid cells. MPO converts hydrogen peroxide to secondary reactive oxygen species (ROS) and is thus primarily considered to induce tissue damage. However, recent studies suggest a protective role of MPO in psoriatic diseases. We aimed to investigate the role of MPO in PsA using the mouse model of mannan-induced PsA. MPO-deficient (Mpo-/-) mice showed exacerbated skin inflammation, joint swelling, and bone degradation associated with increased infiltration of neutrophils, classically activated macrophages, and T cells as well as increased inflammatory cytokine expression in the affected tissues. In the absence or blockade of MPO, in vitro neutrophil stimulation resulted in reduced NET formation and enhanced degranulation characterized by increased neutrophil elastase (NE) activity. In addition, in vitro differentiated macrophages from Mpo-/- mice showed increased interleukin (Il)-6 mRNA expression. Altogether, our findings suggest that MPO controls inflammatory responses in PsA, at least in part, by reducing neutrophil degranulation and serine protease release and, putatively, by reducing inflammatory cytokine production by macrophages.

Keywords: inflammation; myeloperoxidase; neutrophil; psoriatic arthritis.