Leishmania mexicanaPromotes Pain-reducing Metabolomic Reprogramming In Cutaneous Lesions

Abstract

ABSTRACTCutaneous leishmaniasis (CL) is characterized by extensive skin lesions associated with an aggressive inflammatory reaction. Despite the extensive inflammation, CL lesions are usually painless, indicating thatLeishmaniainfection may trigger anti-nociceptive activities in the infected tissues. To this date, the molecular mechanisms responsible for this clinical phenomenon have not been identified. Through an untargeted metabolomic analysis by mass spectrometry, we found enriched anti-nociceptive metabolic pathways in mice infected withLeishmania(L.)mexicana.In particular, endogenous purines were elevated at the lesion site during chronic infection, as well asin vitroin infected macrophages, compared to non-infected mice. These purines have known anti-inflammatory and analgesic properties by acting through adenosine receptors and inhibiting transient receptor potential channels of the vanilloid subtype 1 (TRPV1). Additionally, purine metabolites can promote interleukin (IL)-10 production, with a subsequent decrease in inflammation and pain sensitivity. We also found arachidonic acid metabolism enriched in the ear lesions compared to the non-infected controls. Arachidonic acid is a metabolite of anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These endocannabinoids act on cannabinoid receptors 1 and 2 and TRPV1 channels to exert anti-inflammatory and analgesic effects. Our study provides the first evidence of metabolic pathways upregulated duringL. mexicanainfection that may mediate anti-nociceptive effects experienced by CL patients and identifies macrophages as a source of these metabolites.Graphical abstractL. mexicanainfection promotes the production of purines, as well as endocannabinoid mediators, which could act on different channels of dorsal root ganglia neuron to inhibit nociception.