1. Introduction
Psoriasis is a chronic inflammatory immune-mediated skin disease caused by vascular hyperplasia, abnormal keratinocyte proliferation, and inflammatory cell infiltration into the epidermis and dermis. These extensive inflammatory cell infiltrates include T-lymphocytes, mast cells, macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils (Lebwohl, 2018). Studies on the pathogenesis of psoriasis have greatly increased our understanding of skin immunology and facilitated the introduction of innovative and efficient therapies. However, at present, psoriasis pathogenesis is incompletely understood.
MDSCs are immature heterogeneous myeloid-derived progenitor cells and can be divided into two cell subtypes, mononuclear MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs), also known as granulocytic MDSCs (G-MDSCs) (Bronte et al., 2016; Tcyganov, Mastio, Chen & Gabrilovich, 2018). MDSCs have been demonstrated to modulate immune responses in inflammatory bowel disease (IBD) (Haile et al., 2008; Wang, Ding, Deng, Zheng & Wang, 2020), transplantation (Dugast et al., 2008; Pengam et al., 2019), many types of cancer (Diaz-Montero, Salem, Nishimura, Garrett-Mayer, Cole & Montero, 2009; Hoechst et al., 2008; Youn, Nagaraj, Collazo & Gabrilovich, 2008), and infections (De Santo et al., 2008; Li et al., 2020). Recent studies have revealed the expansion of MDSC populations, which produce cytokines including IL-23, IL-1β, and C-C motif chemokine ligand 4 (CCL4), in patients with psoriasis (Cao et al., 2016; Chen et al., 2020; Oka et al., 2017; Soler & McCormick, 2011). M-MDSCs express high levels of inducible nitric oxide synthase (iNOS), which is a mediator of the suppressive function of M-MDSCs in cancer (Mundy-Bosse et al., 2011). MDSCs function as immune disruptors in patients with systemic lupus erythematosus (SLE) in an iNOS-dependent manner. The number of M-MDSCs and the expression of iNOS decreased after treatment, suggesting that these cells can be used as an indicator of treatment effectiveness (Wang et al., 2019).
IL-35 is a novel inhibitory cytokine, consisting of Epstein-Barr virus-induced gene 3 (EBI3) and IL-12 chain (p35) subunits that belong to the IL-12 cytokine family (Collison et al., 2007). IL-35 has two major effects including the inhibition of T-cell proliferation in various disease models (Kochetkova, Golden, Holderness, Callis & Pascual, 2010; Wirtz, Billmeier, McHedlidze, Blumberg & Neurath, 2011) and inhibition of the development and differentiation of Th17 cells (Collison et al., 2010; Collison, Pillai, Chaturvedi & Vignali, 2009). IL-35 gene therapy significantly alleviated psoriasis-like symptoms in psoriasis mouse models (Zhang et al., 2016). However, the contribution of IL-35 recombinant protein to the pathogenesis of psoriasis is not fully understood. Therefore, in this study, we aimed to investigate the role of the IL-35 recombinant protein in the pathogenesis of psoriasis.