Carbon monoxide decreases endosome–lysosome fusion and inhibits soluble antigen presentation by dendritic cells to <scp>T</scp> cells.

Tardif, Virginie; Riquelme, Sebastián A.; Remy, Séverine; Carreño, Leandro J.; Cortés, Claudia; Thézenas, Simon; Hill, Marcelo; Louvet, Cédric; Riedel, Claudia A.; Blancou, Philippe; Bach, Jean‐Marie; Chauveau, Christine; Bueno, Susan M.; Anegón, Ignacio; Kalergis, Alexis M.

doi:10.1002/eji.201343600

Cited by 33 publications

(53 citation statements)

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“…Thus, mitochondrial dysfunction is not associated with reduced DCs maturation, because the stability of this organelle is not directly associated with these routes. Moreover, this notion agrees with our previous [21] and current report where CO-mediated mitochondrial dysfunction did not impair LPS-induced maturation.Although in a previous report we have shown that CO did not significantly impair OVA degradation [21], here we show single-endosome data supporting that CO can impair antigen processing. An explanation for these apparent discrepancies consists of differences in the experimental settings between studies.…”

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confidence: 94%

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

et al. 2015

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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...

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confidence: 94%

“…1F-G). These results support our previous findings, where CO was unable to dampen these same processes [21], suggesting that mitochondrial function might not be involved in nonantigenic inflammatory routes in DCs. Next, we searched for the mitochondria-independent mechanism that sustained these processes.…”

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confidence: 92%

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

et al. 2015

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“…As previously reported, OVA coupled to Alexa647 and BSA coupled to DQ-Red were used to analyze antigen uptake and antigen degradation, respectively. 18,[22][23][24] The flow cytometry gating strategy from one representative experiment for OVA uptake and BSA degradation by CD11c…”

Section: Size 20 Nm Ps Particles Modulate Antigen Degradation In Bmdcsmentioning

confidence: 99%

Size-dependent accumulation of particles in lysosomes modulates dendritic cell function through impaired antigen degradation

Seydoux¹,

Rothen‐Rutishauser²,

Nita³

et al. 2014

IJN

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Introduction Nanosized particles may enable therapeutic modulation of immune responses by targeting dendritic cell (DC) networks in accessible organs such as the lung. To date, however, the effects of nanoparticles on DC function and downstream immune responses remain poorly understood. Methods Bone marrow–derived DCs (BMDCs) were exposed in vitro to 20 or 1,000 nm polystyrene (PS) particles. Particle uptake kinetics, cell surface marker expression, soluble protein antigen uptake and degradation, as well as in vitro CD4 + T-cell proliferation and cytokine production were analyzed by flow cytometry. In addition, co-localization of particles within the lysosomal compartment, lysosomal permeability, and endoplasmic reticulum stress were analyzed. Results The frequency of PS particle–positive CD11c + /CD11b + BMDCs reached an early plateau after 20 minutes and was significantly higher for 20 nm than for 1,000 nm PS particles at all time-points analyzed. PS particles did not alter cell viability or modify expression of the surface markers CD11b, CD11c, MHC class II, CD40, and CD86. Although particle exposure did not modulate antigen uptake, 20 nm PS particles decreased the capacity of BMDCs to degrade soluble antigen, without affecting their ability to induce antigen-specific CD4 + T-cell proliferation. Co-localization studies between PS particles and lysosomes using laser scanning confocal microscopy detected a significantly higher frequency of co-localized 20 nm particles as compared with their 1,000 nm counterparts. Neither size of PS particle caused lysosomal leakage, expression of endoplasmic reticulum stress gene markers, or changes in cytokines profiles. Conclusion These data indicate that although supposedly inert PS nanoparticles did not induce DC activation or alteration in CD4 + T-cell stimulating capacity, 20 nm (but not 1,000 nm) PS particles may reduce antigen degradation through interference in the lysosomal compartment. These findings emphasize the importance of performing in-depth analysis of DC function when developing novel approaches for immune modulation with nanoparticles.

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“…Despite the encouraging finding that CO produced a marked decrease in IFN-g mRNA levels in kidney, this reduction did not achieve statistical significance (P = 0.0577). In addition, CO treatment would also modulate the activation and maturation of DCs and macrophages leading to reduced levels of proinflammatory cytokines such as IL-6, IL-12 and IL-18, as observed in CO-treated mice [37]. However, the precise contribution of activated B220 1 CD3 1 CD4 2 T cells to kidney and lung injury remains to be elucidated, as well as whether CO could modulate activated T cell recruitment directly in glomerulus.…”

mentioning

confidence: 99%

Carbon monoxide inhibits T cell activation in target organs during systemic lupus erythematosus

Mackern-Oberti

Obreque

Méndez

et al. 2015

Clinical and Experimental Immunology

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SummarySystemic lupus erythematosus is characterized by the presence of circulating anti-nuclear antibodies (ANA) and systemic damage that includes nephritis, haematological manifestations and pulmonary compromise, among others. Although major progress has been made in elucidating the molecular mechanisms responsible for autoimmunity, current therapies for lupus have not improved considerably. Because the exposure of carbon monoxide (CO) has been shown to display beneficial immunoregulatory properties in different immune-mediated diseases, we investigated whether CO therapy improves lupus-related kidney injury in lupus mice. MRL-Fas lpr lupus mice were exposed to CO and disease progression was evaluated. ANA, leucocyteinfiltrating populations in spleen, kidney and lung and kidney lesions, were measured. CO therapy significantly decreased the frequency of activated B220 1 CD4 2 CD8 2 T cells in kidneys and lungs, as well as serum levels of ANA. Furthermore, we observed that CO therapy reduced kidney injury by decreasing proliferative glomerular damage and immune complexes deposition, decreased proinflammatory cytokine production and finally delayed the impairment of kidney function. CO exposure ameliorates kidney and lung leucocyte infiltration and delays kidney disease in MRLFas lpr lupus mice. Our data support the notion that CO could be explored as a potential new therapy for lupus nephritis.

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Carbon monoxide decreases endosome–lysosome fusion and inhibits soluble antigen presentation by dendritic cells to T cells.

Cited by 33 publications

References 61 publications

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

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

Size-dependent accumulation of particles in lysosomes modulates dendritic cell function through impaired antigen degradation

Carbon monoxide inhibits T cell activation in target organs during systemic lupus erythematosus

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