High glucose heightens vulnerability to <i>Leishmania braziliensis</i> infection in human macrophages by hampering the production of reactive oxygen species through TLR2 and TLR4

Diabetes increases susceptibility to infections, including <i>Leishmania braziliensis</i> (<i>Lb</i>). Our group previously demonstrated that diabetic patients with cutaneous leishmaniasis (CL) take longer to heal lesions compared to non-diabetics. Since macrophages play a critical role in CL pathogenesis, we investigated how high glucose levels impact their response during <i>Lb</i> infection. Macrophages cultured in high glucose conditions showed increased parasite load than those in normal glucose conditions. The production of inflammatory mediators was similar between glucose conditions, but basal reactive oxygen species (ROS) production was elevated under high glucose conditions and remained unchanged after <i>Lb</i> infection, indicating glucose-induced oxidative stress does not control the parasite. In contrast, macrophages in normal glucose conditions, exhibited increased ROS production only after infection<i>.</i> Additionally, high glucose reduced TLR2 and TLR4 expression, which was also observed after <i>Lb</i> infection. TLR2/4 inhibition increased <i>Lb</i> infection in normal glucose conditions, mediated by TLR-dependent ROS production. However, this mechanism was absent under high glucose conditions, where elevated basal ROS production appeared TLR-independent. Biopsies from diabetic CL patients corroborated these findings, showing decreased TLR2 and TLR4 expression compared to non-diabetics. These findings suggest that high glucose levels induce oxidative stress and reduces TLR expression, impairing macrophage functions and rendering them less effective at controlling Lb infection.