Monocyte glycolysis determines CD8+ T cell functionality in human Chagas disease.
Chagas disease is a lifelong pathology resulting from Trypanosoma cruzi infection. It represents one of the most frequent causes of heart failure and sudden death in Latin America. Herein, we provide evidence that aerobic glycolytic pathway activation in monocytes drives nitric oxide (NO) production, triggering tyrosine nitration (TN) on CD8+ T cells and dysfunction in patients with chronic Chagas disease. Monocytes from patients exhibited a higher frequency of hypoxia-inducible factor 1α and increased expression of its target genes/proteins. Nonclassical monocytes are expanded in patients' peripheral blood and represent an important source of NO. Monocytes entail CD8+ T cell surface nitration because both the frequency of nonclassical monocytes and that of NO-producing monocytes positively correlated with the percentage of TN+ lymphocytes. Inhibition of glycolysis in in vitro-infected peripheral blood mononuclear cells decreased the inflammatory properties of monocytes/macrophages, diminishing the frequency of IL-1β- and NO-producing cells. In agreement, glycolysis inhibition reduced the percentage of TN+CD8+ T cells, improving their functionality. Altogether, these results clearly show that glycolysis governs oxidative stress on monocytes and modulates monocyte-T cell interplay in human chronic Chagas disease. Understanding the pathological immune mechanisms that sustain an inflammatory environment in human pathology is key to designing improved therapies.
['Sanmarco|Liliana María|LM|', 'Eberhardt|Natalia|N|', 'Bergero|Gastón|G|', 'Quebrada Palacio|Luz Piedad|LP|', 'Adami|Pamela Martino|PM|', 'Visconti|Laura Marina|LM|', 'Minguez|Ángel Ramón|ÁR|', 'Hernández-Vasquez|Yolanda|Y|', 'Carrera Silva|Eugenio Antonio|EA|', 'Morelli|Laura|L|', 'Postan|Miriam|M|', 'Aoki|Maria Pilar|MP|']
D000328:Adult D000818:Animals D018414:CD8-Positive T-Lymphocytes D016022:Case-Control Studies D002450:Cell Communication D014355:Chagas Disease D002522:Chlorocebus aethiops D018920:Coculture Techniques D005260:Female D006019:Glycolysis D006801:Humans D008213:Lymphocyte Activation D008297:Male D008875:Middle Aged D009000:Monocytes D009569:Nitric Oxide D018384:Oxidative Stress D061251:Primary Cell Culture D015800:Protozoan Proteins D014349:Trypanosoma cruzi D014443:Tyrosine D014709:Vero Cells D055815:Young Adult
Monocytes Cardiovascular disease Glucose metabolism Immunology Metabolism