Abstract
Chronic activation of innate immune responses in the brain is increasingly recognized as a contributor to neurodegenerative diseases, including Alzheimer's disease (AD). AD remains a major global health challenge due to the inefficacy of current therapies to modify disease progression. In AD, hyperactivated microglia, the brain's resident macrophages, play a central role by responding to amyloid-beta peptides (Aβ) through activation of the NLRP3 inflammasome, a key innate immune sensor and a promising therapeutic target. Leishmania infantum, a protozoan parasite causing visceral leishmaniasis, is known to employ sophisticated mechanisms to subvert inflammatory responses in macrophages, including modulation of the NLRP3 inflammasome, thus representing a potential natural model for counteracting microglia-related inflammation. However, microglia-Leishmania interactions remain unexplored, particularly the parasite's ability to modulate microglial NLRP3 activation. Here, we demonstrate that L. infantum invades and persists in microglia without inducing cell activation, indicating an immunologically silent entry. Aβ-stimulated NLRP3 activation was suppressed by Leishmania infection, as evidenced by a significant reduction in key pro-inflammatory mediators, including IL-1β, IL-18, TNF-α, and neurotoxic nitric oxide. Mechanistically, L. infantum disrupted NLRP3 priming by interfering with NF-κB signaling and upregulating the negative regulator A20. Additionally, L. infantum limited ASC speck formation, caspase-1 activation and ROS production while preserving lysosomal integrity. These findings reveal, for the first time, an unrecognized inhibitory effect of L. infantum on the microglial NLRP3/NF-κB axis and provide mechanistic insights into the parasite's immune subversion in Aβ-activated microglia. Deciphering the molecular pathways exploited by L. infantum and the specific parasitic effectors involved could offer novel therapeutic targets and bioinspired strategies to mitigate microglial inflammatory responses in the context of AD.