Suppressing the microglia-mediated neuroinflammation in Alzheimer’s disease with Leishmania infantum parasites

Alzheimer’s disease is a progressive, irreversible and yet uncurable brain disorder. Neuroinflammation, mainly mediated by the release of pro-inflammatory mediators by overactivated microglia (the brain’s resident macrophages, MG), might be a vital component in the initiation and progression of AD pathology. Indeed, modulating neuroinflammation through MG-targeted approaches is considered an innovative strategy for AD. In distant human immunopathologies such as visceral leishmaniasis infection, ancient Leishmania infantum parasites (Li) have co-evolved sophisticated mechanisms to survive within macrophages (Mϕ) by inactivating myriads of inflammatory responses that threaten parasite persistence. Among these, our group has demonstrated that Li reduces the activation of the NLRP3 inflammasome (an innate immune sensor) in amyloid-β-treated Mϕ, resulting in the generation of an anti-inflammatory milieu. Being MG functionally similar to Mϕ, we hypothesize that Leishmania subversion tactics against the host immune response might be conserved and exploited to suppress the dysfunctional pro-inflammatory properties of MG in AD. Here, by using immortalized and primary murine MG we found that Li infection did not induce the release of pro-inflammatory mediators, and that the expression of Iba-1 (a marker of AD MG), resulted to be greatly reduced only in Li-dwelling cells. Additionally, we observed that both Li and Aβ can be concomitantly phagocytosed by MG, suggesting enhanced phagocytic activities by infected MG in the presence of Aβ. Finally, we further show that the pro-inflammatory NF-kB/NLRP3 axis is impaired in infected and Aβ-stimulated MG, with the upregulation of the NF-kB-negative regulator A20 as the main mechanistic explanation. Overall, Leishmania infection results in a wide anti-inflammatory phenotype in MG, even under Aβ stimulation, which holds promise for suppressing aberrant MG-mediated inflammatory responses. These results may represent an unprecedented bioinspired strategy against neuroinflammation in AD, with the potential of discovering new molecular targets for therapeutic intervention.