Soluble LILRA3 promotes neurite outgrowth and synapses formation through high affinity interaction with Nogo 66.

Inhibitory proteins, particularly Nogo 66, a highly conserved 66 amino acid loop of Nogo A, play key roles in limiting the intrinsic capacity of the central nervous system to regenerate after injury. Ligation of surface Nogo receptors (NgRs) and/or leukocyte immunoglobulin like receptor B2 (LILRB2) and its mouse orthologue the paired-immunoglobulin-like receptor B (PIRB) by Nogo 66 transduces inhibitory signals that potently inhibit neurite outgrowth. Here we show that soluble leukocyte immunoglobulin-like receptor A3 (LILRA3) is a high affinity receptor for Nogo 66, suggesting that LILRA3 might be a competitive antagonist to these cell surface inhibitory receptors. Consistent with this, LILRA3 significantly reversed Nogo 66-mediated inhibition of neurite outgrowth and promoted synapse formation in primary cortical neurons via regulation of the MEK/ERK pathway. LILRA3 represents a new antagonist to Nogo 66-mediated inhibition of neurite outgrowth in the CNS, a function distinct from its immune-regulatory role in leukocytes. This report is also the first to demonstrate that a member of LILR family normally not expressed in rodents exerts functions on mouse neurons through the highly homologous Nogo 66 ligand.

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