Cathepsin S Inhibition Suppresses Autoimmune-triggered Inflammatory Responses in Macrophages

In several types of antigen-presenting cells (APCs), Cathepsin S (CatS) plays a crucial role in the regulation of MHC class II surface expression and consequently influences antigen (Ag) presentation of APCs to CD4 T cells. During the assembly of MHC class II-Ag peptide complexes, CatS cleaves the invariant chain p10 (Lip10) - a fragment of the MHC class II-associated invariant chain peptide. In this report, we used a selective, high-affinity CatS inhibitor to suppress the proteolytic activity of CatS in lymphoid and myeloid cells. CatS inhibition resulted in a concentration-dependent Lip10 accumulation in B cells from both healthy donors and patients with systemic lupus erythematosus (SLE). Furthermore, CatS inhibition led to a decreased MHC class II expression on B cells, monocytes, and proinflammatory macrophages. In SLE patient-derived peripheral blood mononuclear cells, CatS inhibition led to a suppressed secretion of IL-6, TNFα, and IL-10. In a second step, we tested the effect of CatS inhibition on macrophages being exposed to patient-derived autoantibodies against C1q (anti-C1q) that are known to be associated with severe lupus nephritis. As shown previously, those SLE patient-derived high-affinity anti-C1q bound to immobilized C1q induce a proinflammatory phenotype in macrophages. Using this human in vitro model of autoimmunity, we found that CatS inhibition reduces the inflammatory responses of macrophages as demonstrated by a decreased secretion of proinflammatory cytokines, the downregulation of MHC class II and CD80. In summary, we can show that the used CatS inhibitor is able to block Lip10 degradation in healthy donor- and SLE patient-derived B cells and inhibits the induction of proinflammatory macrophages. Thus, CatS inhibition seems to be a promising future treatment of SLE.