Abstract
Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous myeloid cells that expand in pathologic conditions as cancer, trauma, and infection. Although characterization of MDSCs is continuously revisited, the best feature is their suppressor activity. There are many markers for MDSC identification, it is distinctive that they express inducible nitric oxide synthase (iNOS) and arginase 1, which can mediate immune suppression. MDSCs can have a medullary origin as a result of emergency myelopoiesis, but also can have an extramedullary origin. Early studies on Trypanosoma cruzi infection showed severe immunosuppression, and several mechanisms involving parasite antigens and host cell mediators were described as inhibition of IL-2 and IL-2R. Another mechanism of immunosuppression involving tumor necrosis factor/interferon γ-dependent nitric oxide production by inducible nitric oxide synthase was also described. Moreover, other studies showed that nitric oxide was produced by CD11b+ Gr-1+ MDSCs in the spleen, and later iNOS and arginase 1 expressed in CD11b+Ly6C+Ly6Glo monocytic MDSC were found in spleen and heart of T. cruzi infected mice that suppressed T cell proliferation. Uncontrolled expansion of monocytic MDSCs leads to L-arginine depletion which hinders nitric oxide production leading to death. Supplement of L-arginine partially reverts L-arginine depletion and survival, suggesting that L-arginine could be administered along with anti-parasitical drugs. On the other hand, pharmacological inhibition of MDSCs leads to death in mice, suggesting that some expansion of MDSCs is needed for an efficient immune response. The role of signaling molecules mediating immune suppression as reactive oxygen species, reactive nitrogen species, as well as prostaglandin E2, characteristics of MDSCs, in T. cruzi infection is not fully understood. We review and discuss the role of these reactive species mediators produced by MDSCs. Finally, we discuss the latest results that link the SLAMF1 immune receptor with reactive oxygen species. Interaction of the parasite with the SLAMF1 modulates parasite virulence through myeloid cell infectivity and reactive oxygen species production. We discuss the possible strategies for targeting MDSCs and SLAMF1 receptor in acute Trypanosoma cruzi infection in mice, to evaluate a possible translational application in human acute infections.
Highlights
Reviewed by: Celio Geraldo Freire-de-Lima, Federal University of Rio de Janeiro, Brazil Danilo Ciccone Miguel, State University of Campinas, Brazil
Other studies showed that nitric oxide was produced by CD11b+ Gr-1+ Myeloid-derived suppressor cells (MDSCs) in the spleen, and later inducible nitric oxide synthase (iNOS) and arginase 1 expressed in CD11b+Ly6C+Ly6Glo monocytic MDSC were found in spleen and heart of T. cruzi infected mice that suppressed T cell proliferation
We have described that during acute T. cruzi infection of BALB/c mice infected with the Y strain, the cardiac inflammatory infiltrate involves CD11b+Ly6C+Ly6Glo MMDSC expressing arginase 1 (Arg1) and iNOS, which suppressed T cell proliferation (Cuervo et al, 2008; Cuervo et al, 2011; Carbajosa et al, 2018)
Summary
MDSCs were identified using anti-Gr-1 antibodies that recognized both, Ly6G and Ly6C, surface molecules. There are some markers common to both subsets as Phospho-Signal transducer and activator of transcription 3 (STAT3), CCAAT enhancer-binding protein beta (c/EBP/b), S100 calcium-binding proteins (S100A8 and S100A9), Programmed death-ligand 1 (PD-L1), IL-10, granulocyte-macrophages colony-stimulating factor (GM-CSF), IL-1, (Bronte et al, 2016), and indoleamine 2,3-dioxygenase (IDO) (Zhao et al, 2016). Because some of those markers are not exclusive of MDSCs, the best probe of bona fide MDSCs is their ability to suppress T cell proliferation. It was proposed that subsets expressing MDSC markers that do not suppress proliferation should be described as MDSC-like cells (MDSC-LC) (Bronte et al, 2016)
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