Acidic Microenvironments Found in Cutaneous Leishmania Lesions Curtail NO-Dependent Antiparasitic Macrophage Activity

Abstract

Local tissue acidosis affects anti-tumor immunity. In contrast, data on tissue pH levels in infected tissues and their impact on antimicrobial activity is sparse. In this study, we assessed the pH levels in cutaneous Leishmania lesions. Leishmania major-infected skin tissue displayed pH levels of 6.7 indicating that lesional pH is acidic. Next, we tested the effect of low extracellular pH on the ability of macrophages to produce leishmanicidal NO and to fight the protozoan parasite Leishmania major. Extracellular acidification led to a marked decrease in both NO production and leishmanicidal activity of lipopolysaccharide (LPS) and interferon γ (IFN-γ)-coactivated macrophages. This was not directly caused by a disruption of NOS2 expression, a shortage of reducing equivalents (NAPDH) or substrate (L-arginine), but by a direct, pH-mediated inhibition of NOS2 enzyme activity. Normalization of intracellular pH significantly increased NO production and antiparasitic activity of macrophages even in an acidic microenvironment. Overall, these findings indicate that low local tissue pH can curtail NO production and leishmanicidal activity of macrophages.

Glutamine synthetase expression rescues human dendritic cell survival in a glutamine-deprived environment

“…Bone marrow-derived macrophages (BMDM) were generated from bone marrow cells of wildtype C57BL/6NCrl (Charles River Breeding Laboratories) in Teflon bags containing DMEM medium (Gibco) supplemented with 10% fetal calf serum (FCS) (Sigma-Aldrich), 5% Horse Serum (Cell Concepts) and supernatant of L929 cells containing M-CSF for 7 days at 10% CO 2 as described earlier ( 20 , 21 ).…”

Supramolecular assemblies from antimony(V) complexes for the treatment of leishmaniasis

“…Considering the strong pH dependence of the stability of Sb-G complexes, the pH of the skin appears to be a critical parameter for the release of Sb-G complexes and Sb(V) from the gel. The pH of the stratum corneum of healthy skin is 4.1–5.8, however, the pH was found to increase in lesioned skin (Proksch 2018 ; Frick et al 2022 ). Thus, in healthy intact skin, one would expect a fast release of Sb(V) at the gel-skin interface.…”