CD11b Activation Reduces Myeloid Brain Infiltration and Mitigates Synucleinopathy in a Model of Parkinson's Disease

Abstract

The pathology of Parkinsons disease is defined by -synuclein (-syn) aggregation into neuronal Lewy bodies, which may lead to chronic neuroinflammation and dopaminergic neurodegeneration. Misfolded -syn activates Toll-like receptor signaling in microglia, leading to downstream activation of NF-{kappa}B and subsequent release of pro-inflammatory cytokines. These cytokines recruit pro-inflammatory myeloid cells from circulation, thereby amplifying neuroinflammation. Thus, reducing microglial activation and myeloid cell infiltration has the potential to reduce neuroinflammation and PD pathology. Here, we investigated a targeted immunomodulatory strategy using LA1, a novel, small-molecule agonist of CD11b, a {beta}2 integrin receptor highly and selectively expressed on myeloid cells and microglia. CD11b has key roles in cell adhesion, migration, and phagocytosis. Previous work has demonstrated that CD11b agonism via LA1 transiently enhances integrin-mediated adhesion that limits immune cell transmigration and tissue infiltration. CD11b agonism also suppresses TLR-driven inflammatory signaling and myeloid cell activation. To evaluate its efficacy in vivo, we utilized pre-clinical Parkinsons disease model by stereotaxically delivering AAV2-SYN to induce -synuclein overexpression in the murine midbrain. Mice were treated with oral LA1 for four or eight weeks and analyzed. LA1 treatment significantly reduced microglial activation and decreased brain infiltration of peripheral immune cells, thereby attenuating -synuclein-induced neuroinflammation. These findings suggest that CD11b agonism may offer a dual-action therapeutic approach in Parkinsons disease by dampening pro-inflammatory responses by central and peripheral myeloid cells.