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

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