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.

Trypanosoma cruzi strains cause different myocarditis patterns in infected mice

“…After blood removal by perfusion, parasite DNA was purified from cardiac tissue with the High Pure PCR Template preparation Kit (Roche), and PCR reactions were performed with 100ng of DNA as described Cuervo et al, 2011).…”

Myeloid Derived Suppressor Cells and Their Role in Diseases

“…For example, the inflammatory heart infiltrate from mice infected with Trypanosoma cruzi consisted mainly of CD11b + Ly6G -Ly6C + MDSCs [85]. These cells exhibited a monocytic phenotype and expressed arginase-1 and iNOS, both of which can suppress T-cell proliferation and prevented clearance of the parasite.…”

Myeloid‐derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

“…More recently, these authors reported the predominant induction of M-MDSCs in cardiac lesions of BALB/c mice infected with T. cruzi Y strain. These cells expressing iNOS/arginase-1 use suppressive mechanisms such as NO production and depletion of arginine by arginase-1 [10].In a previous study analyzing the innate immunity induced in BALB/c and C57BL/6 (B6) mice after Tulahuen strain T. cruzi infection [21], we observed that B6 showed higher morbidity and mortality compared with BALB/c mice which demonstrated better tissue repair. In addition, increased and persistent levels of TNF-α, IL-6, IL-12, and IL-1β proinflammatory cytokines and very low IL-10 and TGF-β were present in the liver of B6 mice.…”

“…This shift in iNOS activity most likely reflects the crosstalk of iNOS with other enzymes such as NADPH oxidase to promote the production of peroxynitrites, which inhibits the proliferation and effector function of T cells [2]. MDSCs use several mechanisms in addition to the production of ROS and NO, such as triggering apoptosis of activated T cells by depleting of L-arginine, via arginase [7][8][9][10]. There is also evidence that MDSCs may suppress immune activation by inducing T regulatory cell expansion [11].…”