Targeting the RAGE/miR-185-3p axis enhances anthelmintic therapy and attenuates Angiostrongylus cantonensis–induced neuroinflammation

Angiostrongylus cantonensis is a food-borne parasite that can cause angiostrongyliasis in non-permissive hosts, such as human. The receptor for advanced glycosylation end products (RAGE) is a multi-ligand receptor that binds a wide range of ligands, including members of the S100 family (e.g., S100B), and contributes to neuroinflammation through the upregulation of inflammatory mediators. MicroRNAs (miRNAs) are critically involved in various biological processes in both health and disease, including brain diseases and A. cantonensis infection. Previous study shown that inhibition of miR-185-3p downregulates RAGE expression. Therefore, the aim of this study is to investigate the role of RAGE and miR-185-3p in A. cantonensis -infected mice. In this study, we employed animal infection and treatment experiments, larval recovery, BBB permeability assays, Western blotting, ELISA, ROS and superoxide detection assays, qRT-PCR, and H&E staining. The results revealed that in A. cantonensis -infected mice, RAGE, larval recovery, blood-brain barrier (BBB) permeability, and inflammatory mediators (e.g., TNF-α, IL-1β, IL-17A, COX-2, NF-κB and ROS) levels were increased. However, miR-185-3p levels were decreased in the infected groups. To better understand the modulatory role of RAGE and miR-185-3p in parasitic meningitis, we treated A. cantonensis -infected mice with Azeliragon (a RAGE antagonist), miR-185-3p mimic, or miR-185-3p mimic NC. Larval recovery, BBB permeability, and levels of inflammatory mediators were significantly decreased in the albendazole -only, Azeliragon , miR-185-3p mimic, albendazole–Azeliragon co-treatment, and albendazole –miR-185-3p mimic co-treatment groups, particularly in the albendazole–Azeliragon or albendazole –miR-185-3p mimic co-treatment groups. Our findings revealed the RAGE was upregulated, whereas miR-185-3p was downregulated, in A. cantonensis –infected mice. These alterations were reversed by RAGE downregulation or miR-185-3p overexpression, which in turn suppressed the progression of A. cantonensis –induced inflammation. Our findings indicate that RAGE and miR-185-3p play important regulatory roles in the neuroinflammatory response associated with angiostrongyliasis. Moreover, combination therapy consisting of an anthelmintic agent and a RAGE-targeting intervention enhances the efficacy of anthelmintic treatment while exerting potential additive anti-inflammatory effects, thereby attenuating A. cantonensis –induced brain injury.