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Aicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterized by neurological involvement with onset in utero or in childhood. Here, we analyze peripheral blood samples from patients bearing AGS-causing mutations in ADAR1, RNASEH2B or SAMHD1 using single-cell transcriptomics and targeted metabolomics. Using machine-learning approaches and differential gene expression analysis, we identified a loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch favoring oxidative phosphorylation and glutathione metabolism over glycolysis in monocytes and dendritic cells. Evidences of mitochondrial stress and accumulation of cytosolic double-stranded DNA and RNA were also found. The energy metabolic switch was confirmed at the metabolic level in primary peripheral blood mononuclear cells of AGS patients. Chemical stabilization of HIF-1α using a synthetic drug in in vitro cellular models of AGS, reversed the energy metabolic switch towards glycolysis, attenuated mitochondrial stress, and markedly reduced the IFN response and IP-10 production. We therefore propose that an energy metabolic switch contributes to chronic inflammation in AGS and that targeting this pathway might represent a potential therapeutic approach. Aicardi-Goutières syndrome (AGS) is a brain condition characterized by type I interferon (IFN)-mediated inflammation. Here, the authors demonstrate a negative correlation between the metabolic regulator, HIF-1α, and type-I IFN responses in AGS.

BackgroundIn rheumatoid arthritis (RA), regulatory T cells (Tregs) are defective in their suppressive capacities and fail to control chronic inflammation. TNF- alpha is involved in inhibition of Treg differentiation and activation, likely via activation of TNF type 1 receptor (TNFR1).1 Conversely, activation of TNFR2 on Tregs is critical for their phenotypic and functional stability in the inflammatory environment.2 Moreover, it has been shown that therapeutic TNF blockade with the anti-TNF monoclonal antibody adalimumab restores the potency of Treg cell suppression in RA by binding to membrane TNF- alpha on monocytes and promoting Treg cell expansion through enhanced TNFR2 signaling.3 In the present study we aimed to establish the role of TNFR2 on Tregs in control of inflammation at multiple levels, by: 1) studying the action of TNF on Treg function in the presence and absence of TNFR2 in vitro, 2) testing the severity of a model of skin inflammation in TNFR2KO mice, 3) evaluating the evolution of TNFR2-expressing Treg from RA patients during anti-TNF treatment.Materials and methodsMice deficient in the TNFR2 gene (TNFR2 KO) and TNFR2 lox/lox mice to conditionally delete TNFR2 specifically in Tregs were used. CD4+CD25+Treg cells were purified by magnetic sorting. Cell phenotype was evaluated by flow cytometry. ATP concentrations were determined by luminometry. Skin inflammation was induced by applying an imiquimod-containing ointment, to the skin. Peripheral blood Treg where characterised before and after 3 months of anti-TNF treatment in 10 RA patients.ResultsIn vitro, TNF- alpha enhanced Foxp3 maintenance through TNFR2 signalling in cultured Tregs. In vivo, TNFR2-negative Treg cells, from both TNFR2KO and TNFR2 lox/lox mice, had lower spontaneous suppressive capacities (lower ATP hydrolysis, inhibition of effector T cells proliferation and IFN- gamma production). Compared to wt mice, TNFR2KO mice had enhanced skin-inflammation and decreased Treg frequency in lymph nodes. In RA patients, TNF blockade induced an increase in the frequency of TNFR2-expressing Tregs at 3 months of treatment vs. the baselineConclusionsTNFR2 signalling on Tregs may play a major role in controlling inflammation and can be activated both by TNF- alpha and anti-TNF treatment. Further studies to dissect TNFR2 dependent pathways on Tregs are warranted.ReferencesNie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF- alpha in rheumatoid arthritis. Nat Med2013; 19:322-8.Chen X, Wu X, Zhou Q, et al. TNFR2 is critical for the stabilisation of the CD4+Foxp3+ regulatory T cell phenotype in the inflammatory environment. J Immunol. 2013; 190:1076-84.Nguyen DX, Ehrenstein MR. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis. J Exp Med2016; 213:1241-53.

BackgroundIn rheumatoid arthritis (RA), regulatory T cells (Tregs) are defective in their suppressive capacities and fail to control chronic inflammation. TNF-α is involved in inhibition of Treg differentiation and activation, likely via activation of TNF type 1 receptor (TNFR1).1 Conversely, activation of TNFR2 on Tregs is critical for their phenotypic and functional stability in the inflammatory environment.2 Moreover, it has been shown that therapeutic TNF blockade with the anti-TNF monoclonal antibody adalimumab restores the potency of Treg cell suppression in RA by binding to membrane TNF- α on monocytes and promoting Treg cell expansion through enhanced TNFR2 signaling.3 In the present study we aimed to establish the role of TNFR2 on Tregs in control of inflammation at multiple levels, by: 1) studying the action of TNF on Treg function in the presence and absence of TNFR2 in vitro, 2) testing the severity of a model of skin inflammation in TNFR2KO mice, 3) evaluating the evolution of TNFR2-expressing Treg from RA patients during anti-TNF treatment.Materials and methodsMice deficient in the TNFR2 gene (TNFR2 KO) and TNFR2 lox/lox mice to conditionally delete TNFR2 specifically in Tregs were used. CD4+CD25+Treg cells were purified by magnetic sorting. Cell phenotype was evaluated by flow cytometry. ATP concentrations were determined by luminometry. Skin inflammation was induced by applying an imiquimod-containing ointment, to the skin. Peripheral blood Treg where characterised before and after 3 months of anti–TNF treatment in 10 RA patients.ResultsIn vitro, TNF-α enhanced Foxp3 maintenance through TNFR2 signalling in cultured Tregs. In vivo, TNFR2-negative Treg cells, from both TNFR2KO and TNFR2 lox/lox mice, had lower spontaneous suppressive capacities (lower ATP hydrolysis, inhibition of effector T cells proliferation and IFN-γ production). Compared to wt mice, TNFR2KO mice had enhanced skin-inflammation and decreased Treg frequency in lymph nodes. In RA patients, TNF blockade induced an increase in the frequency of TNFR2-expressing Tregs at 3 months of treatment vs. the baselineConclusionsTNFR2 signalling on Tregs may play a major role in controlling inflammation and can be activated both by TNF-α and anti-TNF treatment. Further studies to dissect TNFR2 dependent pathways on Tregs are warranted.ReferencesNie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med2013;19:322-8.Chen X, Wu X, Zhou Q, et al. TNFR2 is critical for the stabilisation of the CD4+Foxp3+ regulatory T cell phenotype in the inflammatory environment. J Immunol. 2013;190:1076-84.Nguyen DX, Ehrenstein MR. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis. J Exp Med2016;213:1241-53.

Aicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterised by neurological involvement with onset in childhood. Chronic inflammation in response to uncontrolled type I IFN production is, among other things, associated with IP-10 secretion. We analysed, at the single-cell transcriptomic levels, peripheral blood samples from patients bearing AGS-causing mutations in SAMHD1, RNASEH2B or ADAR1 genes. Using machine-learning approaches and differential gene expression we identified a drastic loss of transcription factor hypoxia induced factor 1 alpha (HIF-1a) expression and activity associated with features of a metabolic switch and mitochondrial stress in monocytes/dendritic cells. Chemical stabilization of HIF-1a, with a synthetic drug in an in vitro model of AGS, allowed us to reverse the energy metabolic switch, attenuate mitochondrial stress and markedly reduce IP-10 production. We therefore propose that energy metabolic switch contributes to exacerbated chronic inflammation in AGS, and that targeting this pathway might represent a promising therapeutic approach.Competing Interest StatementM.M.M. and M.B. are listed as inventors on a patent application related to this article (European Patent Application no.EP23305153.1, entitled Use of HIF-1 stabilizing agents for the treatment of type I interferonopathies).

Abstract SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κB activity, TNF-α signaling, associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology. Competing Interest Statement The authors have declared no competing interest. Footnotes * Pediatric-Biocovid Study Group: François Angoulvant, Camille Aupiais, Fanny Bajolle, Romain Basmaci, Paul Bastard, Matthieu Bendavid, Solène Blache, Stéphane Blanche, Christine Bodemer, Martin Chalumeau, Lucienne Chatenou, Anne Chauviré-Drouard, Fleur Cohen-Aubart, Agathe Debray, Simon Albert Faye, Simon Fillatreau, Jacques Fourgeaud, Pierre Frange, Marion Grimaud, Lucile Houyel, Diala Khraiche, Hanane Kouider, Alain Lefevre-Utile, Pierre-Louis Leger, Morgane Le Gouez, Michael Levy, Manon Marchais, Soraya Matczak, Alexis Mathian, Bénédicte Neven, Perrine Parize, Olivier Pellé, Yael Pinhas, Marie Pouletty, Pierre Quartier dit Maire, Sylvain Renolleau, Anne-Sophie Romain, Laure de Saint-Blanquat, Isabelle Sermet, Melissa Taylor.