Abstract
Apolipoprotein A-I binding protein (AIBP) reduces lipid raft abundance by augmenting the removal of excess cholesterol from the plasma membrane. Here, we report that AIBP prevents and reverses processes associated with neuroinflammatory-mediated spinal nociceptive processing. The mechanism involves AIBP binding to Toll-like receptor-4 (TLR4) and increased binding of AIBP to activated microglia, which mediates selective regulation of lipid rafts in inflammatory cells. AIBP-mediated lipid raft reductions downregulate LPS-induced TLR4 dimerization, inflammatory signaling, and expression of cytokines in microglia. In mice, intrathecal injections of AIBP reduce spinal myeloid cell lipid rafts, TLR4 dimerization, neuroinflammation, and glial activation. Intrathecal AIBP reverses established allodynia in mice in which pain states were induced by the chemotherapeutic cisplatin, intraplantar formalin, or intrathecal LPS, all of which are pro-nociceptive interventions known to be regulated by TLR4 signaling. These findings demonstrate a mechanism by which AIBP regulates neuroinflammation and suggest the therapeutic potential of AIBP in treating preexisting pain states.
Highlights
Apolipoprotein A-I binding protein (AIBP) is a secreted protein discovered in a screen of proteins that physically associate with ApoA-I (Ritter et al, 2002)
We hypothesized that AIBP can regulate Toll-like receptor-4 (TLR4) residing in lipid rafts via binding to the receptor and recruiting ApoA-I or HDL to TLR4-occupied lipid rafts
We demonstrated constitutive AIBP binding to the TLR4 ectodomain, but nott to ectodomains of TLR1, TLR7 or TLR9 (Fig. 1A and Fig. S1A)
Summary
Apolipoprotein A-I binding protein (AIBP) is a secreted protein discovered in a screen of proteins that physically associate with ApoA-I (Ritter et al, 2002). AIBP has been shown to bind ApoA-I and HDL (Fang et al, 2013; Ritter et al, 2002) and augment cholesterol efflux from endothelial cells and macrophages (Fang et al, 2013; Zhang et al, 2016). Activated Toll-like receptor-4 (TLR4) localizes to lipid rafts and its function critically depends on integrity of rafts, where decreased diffusion rates provide optimal conditions for TLR4 dimerization, an obligatory step in initiation of its signaling cascade (Fessler and Parks, 2011; Schmitz and Orso, 2002; Tall and Yvan-Charvet, 2015). We hypothesized that AIBP-mediated increases in cholesterol efflux should interfere with TLR4-dependent inflammatory signaling
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