Normalization of cholesterol metabolism in spinal microglia alleviates neuropathic pain

Abstract

Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naive mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1–deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia or reverse CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling the TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.

Reduced AIBP expression in bronchial epithelial cells of asthmatic patients: Potential therapeutic target

“…Modified, His‐tagged AIBP, 7 designated as RFT1081, was developed by Raft Pharmaceuticals and custom produced by Selvita, Inc. (Cambridge, MA). In brief, RFT1081 contains an N‐terminal extension, including His tag, which augments anti‐inflammatory properties of AIBP.…”

“…Similar to measuring pharmacokinetics of intrathecally delivered AIBP in spinal cord and CSF, 7 to measure RFT1081 exposure in lung and BAL, we used Apoa1bp −/− mice in order to avoid cross‐reactivity of the antibodies we use with endogenous mouse AIBP in the lung tissue. Plates were coated with BE‐1 anti‐AIBP monoclonal antibody (5 µg/mL), incubated for 3h with BAL, plasma or lung extract samples and detected with a rabbit polyclonal anti‐AIBP antibody (gift from Dr. Longhou Fang, Houston Methodist Research Institute), followed by a goat‐anti‐rabbit‐ALP antibody (Sigma Aldrich) and LumiPhos 530 (Lumigen); luminescence was measured using a plate reader (BioTek).…”

“…Because administration of AIBP, either as a recombinant protein or via adeno‐associated virus delivery, produced anti‐inflammatory and protective effects in neuroinflammation and neuropathic pain, 7 vascular inflammation and atherosclerosis 3 and acute lung injury 4 ; in this work, we examined whether lung expression of endogenous AIBP is affected in asthma patients and if inhaled AIBP can reduce pulmonary inflammation and alleviate airway hyperresponsiveness in a mouse model of asthma.…”

“…Because endogenous AIBP expression was reduced in asthma (Figure 1A-G) and because of the broad anti-inflammatory protections afforded by AIBP in the lung, 4 and other tissues, 3,7 we tested whether intranasal delivery of recombinant AIBP (RFT1081 produced by Raft Pharmaceuticals) will have a therapeutic effect in a mouse model of asthma.…”

Bioinformatics Analysis of the MicroRNA-Metabolic Gene Regulatory Network in Neuropathic Pain and Prediction of Corresponding Potential Therapeutics

“…Metabolism plays a major role in multiple biological processes. Studies state that metabolic dysregulation plays a central role in painful peripheral neuropathies, and there is cross-communication between metabolism, inflammation, and immune response in NP (Navia-Pelaez et al 2021 ). Previous studies have shown that CCI-induced NP causes metabolic changes in serum and spinal cord (Chen et al 2021 ); changes in metabolism of thalamic neurotransmitters have also been reported (Wang et al 2020 ).…”