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Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells

Cellular & Molecular Immunology volume 12, pages 384–386 (2015)Cite this article

Tolerogenic dendritic cells (DCs) are widely studied for their possible use in the treatment of inflammatory disorders, such as autoimmune diseases. One of the obstacles for the use of this cell-based therapy is the characterization of drugs that are able to modulate DCs. We have previously shown that chloroquine (CQ), an antimalarial agent, has the ability to modulate DCs towards a tolerogenic phenotype.1 These tolerogenic DCs are able to suppress the development of experimental autoimmune encephalomyelitis (EAE), a T cell-driven mouse model of human multiple sclerosis. In addition, several studies have proposed that nitric oxide (NO) plays a major role in the differentiation of regulatory T cells (Tregs) and the suppression of Th1/Th17 cells.2,3 However, little is known about the role of DC-derived NO in the modulation of inflammatory autoimmune responses. Thus, we aimed to evaluate whether NO plays a role in the tolerogenic activity of CQ-treated DCs (CQ-DCs). We found that CQ induces DC production of NO and expression of indoleamine 2,3-dioxygenase (IDO), as well as inducible nitric oxide synthase (iNOS). In addition, CQ-DCs stimulated the differentiation of Tregs at the expense of Th1/Th17 cells. On the other hand, iNOS−/− DCs did not acquire a tolerogenic phenotype following CQ treatment. Rather, CQ-DCsiNOS−/− stimulated the differentiation of Th1/Th17 cells as well as Tregs. In a therapeutic approach, CQ-DCsiNOS−/− were unable to suppress the development of EAE. Gene expression analyses of central nervous system (CNS) tissue from mice that received CQ-DCsiNOS−/− showed an increased expression of inflammatory modulators compared with mice that received CQ-DCsWT. In this work, we show that NO is an important factor in the modulatory activity of tolerogenic dendritic cells.

DCs are antigen-presenting cells that can dictate the course of the immune response via the modulation and activation of naive T cells. DC modulation is a possible approach to address the immunosuppression that is often caused by tumors4 and the exacerbated immune response observed in autoimmune diseases.5 Multiple sclerosis, one such autoimmune disease, is a debilitating condition that affects the CNS. Studies in EAE, an experimental mouse model of multiple sclerosis, have found that much of the immunological etiology of the disease development is due to the activity of Th1/Th17 cells, and these studies have found that NO plays a major role in disease progression.2

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Acknowledgements

This work was supported by the São Paulo Research Foundation (FAPESP, grant nos. 2011/17965-3 and #2013/08194-9). RT received a FAPESP scholarship (grant no. 2014/02631-0).

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  1. Department of Structural and Functional Biology, Institute of Biology, University of Campinas, SP, Brazil

    Liana Verinaud, Luidy Kazuo Issayama, Fábio Zanucoli, Ana Carolina de Carvalho, Thiago Alves da Costa, Rosária Di Gangi, Amanda Pires Bonfanti, Isadora Tassinari Ferreira, Alexandre Leite Rodrigues de Oliveira, Dagmar Ruth Stach Machado & Rodolfo Thomé

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  1. Liana Verinaud
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Correspondence to Rodolfo Thomé.

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Verinaud, L., Issayama, L., Zanucoli, F. et al. Nitric oxide plays a key role in the suppressive activity of tolerogenic dendritic cells. Cell Mol Immunol 12, 384–386 (2015). https://doi.org/10.1038/cmi.2014.94

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