Heme-oxygenase 1 (HO-1) prevents T cell-mediated inflammatory disease by producing carbon monoxide (CO) and impairing DC immunogenicity. However, the cellular mechanisms causing this inhibition are unknown. Here, we show that CO impairs mitochondrial function in DCs by reducing both the mitochondrial membrane potential and ATP production, and resembling the effect of a nonlethal dose of a classical mitochondria uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Moreover, both CO and CCCP reduced cargo transport, endosome-to-lysosome fusion, and antigen processing, dampening the production of peptide-MHC complexes on the surface of DCs. As a result, the inhibition of naive CD4 + T-cell priming was observed. Furthermore, mitochondrial dysfunction in DCs also significantly reduced CD8 + T cell-dependent type 1 diabetes onset in vivo. These results showed for the first time that CO interferes with T-cell priming by blocking an unknown mitochondria-dependent antigen-processing pathway in mature DC. Interestingly, other immune functions in DCs such as antigen capture, cytokine secretion, costimulation, and cell survival relied on glycolysis, suggesting that oxidative phosphorylation might only play a key role for the maturation of antigen-containing endosomes. In conclusion, CO produced by HO-1 impairs antigen-dependent inflammation by regulating DC immunogenicity by a mitochondria-dependent mechanism.Keywords: Antigen presentation r Carbon monoxide r Dendritic cell r Endosome r Hemeoxygenase 1 r Mitochondria Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDCs are professional APCs able to recognize, endocytose, process, and present soluble antigens to naïve T cells [1][2][3][4][5][6][7]. A tight regulation of these processes defines whether these cells promote eitherCorrespondence: Dr. Alexis M. Kalergis and Dr. Susan Bueno e-mail: akalergis@bio.puc.cl; akalergis@icloud.com; sbueno@bio.puc.cl immunity or tolerance [1,[8][9][10][11][12]. Due to these features of DCs, in the last years significant efforts have been made to define the molecular and cellular elements that modulate their function [13]. Along these lines, mature DCs are better APCs than immature DCs [1,10,12,13] because the former more efficiently display antigenderived peptide-MHC complexes (pMHCs, signal 1) [5,14], costimulatory molecules (signal 2) [3,5], and cytokine secretion (signal 3) [1,13]. Lack of any of these signals on DCs leads to C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 3270 Sebastián A. Riquelme et al. Eur. J. Immunol. 2015. 45: 3269-3288 an inefficient activation of naïve T cells and reduced inflammation [1,13,15]. Several inflammatory pathologies are mediated by de novo generation of auto or alloantigen-specific T cells, which require priming by DCs [8,16]. Thus, modulation of DCs is considered as a promising therapeutic strategy to either treat or prevent inflammatory/autoimmune diseases [17]. Among several regulatory mol...

Antigen-presenting cells (APCs) including dendritic cells (DCs) play a critical role in the development of autoimmune diseases by presenting self-antigen to T-cells. Different signals modulate the ability of APCs to activate or tolerize autoreactive T-cells. Since the expression of heme oxygenase-1 (HO-1) by APCs has been associated with the tolerization of autoreactive T-cells, we hypothesized that HO-1 expression might be altered in APCs from autoimmune-prone non-obese diabetic (NOD) mice. We found that, compared to control mice, NOD mice exhibited a lower percentage of HO-1-expressing cells among the splenic DCs, suggesting an impairment of their tolerogenic functions. To investigate whether restored expression of HO-1 in APCs could alter the development of diabetes in NOD mice, we generated a transgenic mouse strain in which HO-1 expression can be specifically induced in DCs using a tetracycline-controlled transcriptional activation system. Mice in which HO-1 expression was induced in DCs exhibited a lower Type 1 Diabetes (T1D) incidence and a reduced insulitis compared to non-induced mice. Upregulation of HO-1 in DCs also prevented further increase of glycemia in recently diabetic NOD mice. Altogether, our data demonstrated the potential of induction of HO-1 expression in DCs as a preventative treatment, and potential as a curative approach for T1D.

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