Targeting dendritic cell inhibitory receptors to down regulate immune response in inflammatory disease

Abstract

Abstract Immune regulator receptors play a crucial role in immune homeostasis by balancing activating vs inhibitory immune responses and are distributed across cells of myeloid and lymphoid lineages. Inhibitory receptors contain Immune Receptor Tyrosine-based Inhibitory Motifs (ITIM) and suppress immune response via SH2 domain-containing protein tyrosine phosphatases (SHP2). Dendritic Cell Inhibitory Receptor (DCIR) is a C-type lectin receptor expressed on monocytes, dendritic cells, and neutrophils. It has been implicated in controlling autoimmunity in preclinical models and polymorphisms linked to patients’ susceptibility to autoimmune diseases such as RA, Lupus, and Sjogren’s. Hence ligation of DCIR using monoclonal antibodies may provide inhibitory signals and therapeutic benefit. Here we show that agonistic anti-human DCIR antibodies (mAb) induce DCIR ITIM phosphorylation and SHP2 association. The DCIR/SHP2 complex diminished the SHP2 association of Syk with FcgR to inhibit TNFa, IL-1b, and IL-6 in human myeloid cells by attenuating the phosphorylation of SHP2, Syk, p38 and p65. Proteomic and RNAseq analyses also suggest that MAPK pathways are regulated by the agonistic mAbs. In human DCIR knock-in mice: (i) DCIR+ cells were enriched in inflamed crypts in DSS-induced colitis model; (ii) Agonistic mAbs reversed the weight loss and reduced the accumulation of neutrophils in the inflamed colon; (iii) Agonistic mAbs significantly reduced the recruitment of neutrophils and leukocytes in zymosanD-induced peritonitis model. Moreover, the increase of DCIR in activated neutrophils can be targeted by mAbs for their clearance. In summary, anti-DCIR agonistic mAbs modulate inhibitory functions and dampen inflammatory responses.