Leukocyte immunoglobulin-like receptor A3 (LILRA3) displays anti-inflammatory and neuro-regenerative functions through interaction with multiple ligands

Abstract

Abstract LILRA3 belongs to a family of highly homologous surface activating and inhibitory receptors that are emerging as critical regulators of immune cell activation by transducing opposing signals. Uniquely, LILRA3 is soluble and so cannot transduce intracellular signals, hence its functions are unknown, despite its ubiquitous presence in sera and its strong clinical association with various inflammatory diseases. This is primarily due lack of knowledge of its ligands, absence of a LILRA3 homolog in rodents and difficulties in producing functional protein. We produced full-length rLILRA3 protein typical of the native protein and used it in a proteomic approach to concurrently identify two novel ligands; LAMR1 and Nogo 66, and one known MHC I ligand, HLA-B2705 that were validated by expression cloning. Importantly, LAMR1 and Nogo 66 independently interacted with LILRA3 with high affinities of 9.1 pmol and 22 pmol respectively. LAMR1 is a multifunctional protein involved in LPS-induced inflammation and HLA-B2705 is strongly associated with seronegative arthritis (SpA). Nogo 66 is potent inhibitors of neurite outgrowth in the central nervous system. We discovered that LILRA3 promoted neurite outgrowth and synapse formation in central nervous system by blocking Nogo 66; strongly suppressed LPS-mediated inflammation in vivo via interaction with LAMR1, and inhibited activation of peripheral blood T cell by competitively blocking interaction of HLA-B2705 with a closely related activating receptor (LILRA1) which is highly expressed on a subset of T cells in HLA-B27 +ve patients with SpA. These results led to a new concept that LILRA3 may bind multiple ligands with varying affinities and display clinically relevant tissue-specific functions.