title: Myeloid-derived suppressor cells infiltrate the heart in acute Trypanosoma cruzi infection.
abstract: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects several million people in Latin America. Myocarditis, observed in the acute and chronic phases of the disease, is characterized by a mononuclear cell inflammatory infiltrate. We previously identified a myeloid cell population in the inflammatory heart infiltrate of infected mice that expressed arginase I. In this study, we purified CD11b(+) myeloid cells from the heart and analyzed their phenotype and function. Those CD11b(+) cells were ∼70% Ly6G(-)Ly6C(+) and 25% Ly6G(+)Ly6C(+). Moreover, purified CD11b(+)Ly6G(-) cells, but not Ly6G(+) cells, showed a predominant monocytic phenotype, expressed arginase I and inducible NO synthase, and suppressed anti-CD3/anti-CD28 Ab-induced T cell proliferation in vitro by an NO-dependent mechanism, activity that best defines myeloid-derived suppressor cells (MDSCs). Contrarily, CD11b(+)Ly6G(+) cells, but not CD11b(+)Ly6G(-) cells, expressed S100A8 and S100A9, proteins known to promote recruitment and differentiation of MDSCs. Together, our results suggest that inducible NO synthase/arginase I-expressing CD11b(+)Ly6G(-) myeloid cells in the hearts of T. cruzi-infected mice are MDSCs. Finally, we found plasma l-arginine depletion in the acute phase of infection that was coincident in time with the appearance of MDSCs, suggesting that in vivo arginase I could be contributing to l-arginine depletion and systemic immunosuppression. Notably, l-arginine supplementation decreased heart tissue parasite load, suggesting that sustained arginase expression through the acute infection is detrimental for the host. This is, to our knowledge, the first time that MDSCs have been found in the heart in the context of myocarditis and also in infection by T. cruzi.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Henar
authors.initials: H
authors.lastname: Cuervo
authors.forename: Néstor A
authors.initials: NA
authors.lastname: Guerrero
authors.forename: Sofía
authors.initials: S
authors.lastname: Carbajosa
authors.forename: Alain
authors.initials: A
authors.lastname: Beschin
authors.forename: Patrick
authors.initials: P
authors.lastname: De Baetselier
authors.forename: Núria
authors.initials: N
authors.lastname: Gironès
authors.forename: Manuel
authors.initials: M
authors.lastname: Fresno
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000097:blood; D039481:CD11b Antigen / Q000096:biosynthesis; D002469:Cell Separation; D002598:Chagas Cardiomyopathy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014349:Trypanosoma cruzi / Q000276:immunology
chemical_list: D039481:CD11b Antigen; D012333:RNA, Messenger; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C544448:Arg1 protein, mouse; D001119:Arginase