Carbon monoxide impairs mitochondria‐dependent endosomal maturation and antigen presentation in dendritic cells

Abstract

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...

Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

“…However, it remains unclear how and where mitochondria could be regulating antigen‐dependent immunity and whether endogenously produced CO can regulate these processes. Recent data from our laboratory propose a role for mitochondria in the transport and processing of antigen‐containing vesicles . These observations suggest that the HO‐1–CO system inhibits this pathway by dropping down mitochondrial ATP production without impairing the glycolysis‐dependent DC maturation .…”

“…Recent data from our laboratory propose a role for mitochondria in the transport and processing of antigen-containing vesicles. 99 These observations suggest that the HO-1-CO system inhibits this pathway by dropping down mitochondrial ATP production without impairing the glycolysis-dependent DC maturation. 99 As a consequence, CO impairs mitochondrial function in DCs up to a point of down-modulating antigen-specific T-cell priming.…”

“…99 These observations suggest that the HO-1-CO system inhibits this pathway by dropping down mitochondrial ATP production without impairing the glycolysis-dependent DC maturation. 99 As a consequence, CO impairs mitochondrial function in DCs up to a point of down-modulating antigen-specific T-cell priming. Because DCs link the innate and the adaptive immune responses, their important function could be modulated by targeting the inflammatory activity of mitochondria by using molecules that regulate ROS and ATP production.…”

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“…Another example of the immunosuppressive role of HO-1 was described by Riquelme et al (2015), who suggest HO-1 prevents T-cell-mediated inflammatory disease by producing CO and impairing DC immunogenicity. CO has been shown to impair the mitochondrial function in DCs by reducing both the mitochondrial membrane potential and ATP production.…”