Gut dysbiosis has been associated with lupus pathogenesis, and fecal microbiota transfers (FMT) from lupus-prone mice shown to induce autoimmune activation into healthy mice. The immune cells of lupus patients exhibit an increased glucose metabolism and treatments with 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, are therapeutic in lupus-prone mice. Here, we showed in two models of lupus with different etiologies that 2DG altered the composition of the fecal microbiome and associated metabolites. In both models, FMT from 2DG-treated mice protected lupus-prone mice of the same strain from the development of glomerulonephritis, reduced autoantibody production as well as the activation of CD4+ T cells and myeloid cells as compared to FMT from control mice. Thus, we demonstrated that the protective effect of glucose inhibition in lupus is transferable through the gut microbiota, directly linking alterations in immunometabolism to gut dysbiosis in the hosts.
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by high morbidity and mortality and its treatment remains challenging. Inflammatory dendritic cells (DCs) have been shown to participate in the initiation and perpetuation of lupus pathogenesis, and tolerogenic DCs have a potential for cell-based therapy in this condition. The mannose receptor (MR, CD206) is a C-type lectin expressed by DCs and its cross-linking induces anti-inflammatory immunosuppressive effects. D-Mannose is a C-2 epimer of glucose that exhibit immunoregulatory effect in models of autoimmune diseases, such as type 1 diabetes and lung airway inflammation. However, the function of D-Mannose treatment in lupus remains unknown.
Methods
B6.MRL-Fas(lpr) (B6.lpr) mice at 4 months of age were treated with D-Mannose in drinking-water for 2 months. Autoantibody production and immune cell activation were compared between the two groups. In vitro, GM-CSF bone marrow-derived dendritic cells (BMDCs) from non-autoimmune B6 mice were cultured for 5 days to generate mature dendritic cells. On day 5, BMDCs were treated with 10 mM glucose (G10) or 10 mM Mannose (M10) for 24 hour and pulsed with LPS for an additional 4 hour. Surface markers and cytokines secretion of BMDCs were analyzed.
Results
The D-Mannose treatment significantly decreased serum anti-dsDNA antibody at week 4. It also increased the percentage of naïve T (Tn) cells and decreased CD4 +T cell activation measured as CD44 +expression. Follicular helper T (TFH) cells/follicular regulatory T (TFR) cells ratio was reduced after D-Mannose treatment. The low frequency of regulatory T (Treg) cells in B6/lpr mice was also expanded after treatment. Besides, D-Mannose treatment increased CD206 expression on spleenic DCs. In vitro experiments showed that D-Mannose promoted a tolerogenic phenotype in BMDCs by decreasing the expression of activation markers (CD40, CD80, CD86) and promoting that of inhibitory markers (CD206 and CD64) expression in B6 mice. Additionally, D-Mannose reduced inflammatory cytokine secretion in BMDCs.
Conclusions
D-Mannose ameliorates the development of lupus-like disease in the B6/lpr mouse model, which may be due to the induction of tolerogenic DCs.
Funding Source(s):
National Key R and D Program of China (2017YFC0909000)
Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoantibodies induce tissue damage including the kidney. Gut microbial dysbiosis contributes to SLE pathogenesis. An abnormal metabolism is a characteristic feature of SLE in which the inflammatory functions of CD4+ T cells rely on glycolysis. We have shown that treatment with 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, reduced the expansion of germinal centers and eliminated the production of autoantibodies, ameliorating disease in lupus-prone mice, including (NZB × NZW)F1 and (NZW x BXSB)F1. Here we show that the 2DG treatment also maintained gut bacterial diversity, reduced the changes in bacterial populations that occurred as disease developed in these mice, and that it altered the distribution of fecal metabolites. We investigated the effect of fecal microbiota transplantation (FMT) from 2DG-treated or control mice into pre-autoimmune lupus-prone mice of the same strain. In both strains, FMT from 2DG-treated mice was highly protective, with a reduction or elimination of anti-dsDNA IgG production, immune cell activation, and renal pathology compared to FMT from control mice. Overall, our results demonstrated for the first time that the therapeutic effect of glucose inhibition in lupus is transferable through the gut microbiota. This implicates either a direct effect of glucose on pathogenic gut bacteria, or an indirect effect through the immune system normalized by glucose inhibition. Supported b R01 AI143313
Pasquine Saule and Isabelle WolowczukTan-Sothea Ouk, Anne Delanoye, Claudie Verwaerde, Laurence Macia, Myriam Delacre, Georges Abboud,http://www.jimmunol.org/content/177/9/5997J Immunol€2006; 177:5997-6006; ;Referenceshttp://www.jimmunol.org/content/177/9/5997.full#ref-list-1This article cites 54 articles, 15 of which you can access for free at: Subscriptionshttp://jimmunol.org/subscriptionsInformation about subscribing to The Journal of Immunology is online at: Permissionshttp://www.aai.org/ji/copyright.htmlSubmit copyright permission requests at: Email Alertshttp://jimmunol.org/cgi/alerts/etocReceive free email-alerts when new articles cite this article. Sign up at:
Abstract Follicular helper T (T FH ) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. Eliminating T FH cells would, however compromise the production of protective antibodies against viral and bacterial pathogens. Here we show that inhibiting glucose metabolism results in a drastic reduction of the frequency and number of T FH cells in lupus-prone mice. However, this inhibition has little effect on the production of T-cell-dependent antibodies following immunization with an exogenous antigen or on the frequency of virus-specific T FH cells induced by infection with influenza. In contrast, glutaminolysis inhibition reduces both immunization-induced and autoimmune T FH cells and humoral responses. Solute transporter gene signature suggests different glucose and amino acid fluxes between autoimmune T FH cells and exogenous antigen-specific T FH cells. Thus, blocking glucose metabolism may provide an effective therapeutic approach to treat systemic autoimmunity by eliminating autoreactive T FH cells while preserving protective immunity against pathogens.
Abstract Background: T follicular helper CD4+ cells (Tfh) are essential for maintenance of systemic lupus erythematosus (SLE) as they help germinal center B cells generate high affinity auto-antibodies. The activation of STAT3 is critical for generation of Tfh cells as it promotes the transcription of BCL6 (the essential transcription factor for Tfh cell differentiation). It is recognized that activated, proliferating SLE CD4+ T cells, contain more iron than controls. Iron binds CDK1 to accentuate JAK1 phosphorylation and activation of STAT3 in proliferating cells. Whether increased iron content of SLE CD4+ T cells augments JAK1-STAT3 signaling and their differentiation into Tfh cells has not been investigated. Experiments: RNAseq and qPCR was used to compare iron regulatory pathways in purified Tfh cells from WT and SLE-prone mice. Labile iron (bio-active) content was measured in freshly isolated Tfh cells. The effect of iron chelator on in vitro Tfh differentiation and effector function was evaluated. Results: Compared to WT, SLE Tfh cells displayed significant increase in genes associated with iron uptake and transmembrane iron transport. Labile iron content and CDK1 gene expression were elevated in SLE Tfh cells. Iron chelation attenuated STAT3 activation, BCL6 expression and IL-21 production in in vitro generated Tfh cells. Conclusion: Our novel data identify an essential role of iron in Tfh cell differentiation and effector function. Increased iron and CDK1 may amplify JAK1-STAT3 signaling and potentiate Tfh cell differentiation. This can be blocked by restricting free iron availability. Understanding this aspect of Tfh cell biology in SLE may support strategies that control labile iron as potential adjunct therapy. Supported by grants from Vifor Pharma (P0213104, P0226952) to Yogesh Scindia NIH (R01AI135128) to Borna Mehrad NIH (R01AI128901) to Laurence Morel
How tissue-specific anatomical distribution and phenotypic specialization are linked to protective efficacy of memory T cells against reinfection is unclear. Here, we show that lung environmental cues program recently recruited central-like memory cells with migratory potentials for their tissue-specific functions during lethal respiratory virus infection. After entering the lung, some central-like cells retain their original CD27hiCXCR3hi phenotype, enabling them to localize near the infected bronchiolar epithelium and airway lumen to function as the first line of defense against pathogen encounter. Others, in response to local cytokine triggers, undergo a secondary program of differentiation that leads to the loss of CXCR3, migration arrest, and clustering within peribronchoarterial areas and in interalveolar septa. Here, the immune system adapts its response to prevent systemic viral dissemination and mortality. These results reveal the striking and unexpected spatial organization of central- versus effector-like memory cells within the lung and how cooperation between these two subsets contributes to host defense.
Patients with systemic lupus erythematosus (SLE) present a high incidence of atherosclerosis, which contributes significantly to morbidity and mortality in this autoimmune disease. An impaired balance between regulatory (Treg) and follicular helper (Tfh) CD4+ T cells is shared by both diseases. However, whether there are common mechanisms of CD4+ T cell dysregulation between SLE and atherosclerosis remains unclear. Pre-B cell leukemia transcription factor 1 isoform d (Pbx1d) is a lupus susceptibility gene that regulates Tfh cell expansion and Treg cell homeostasis. Here, we investigated the role of T cells overexpressing Pbx1d in low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed with a high-fat diet, an experimental model for atherosclerosis. Pbx1d-transgenic T cells exacerbated some phenotypes of atherosclerosis, which were associated with higher autoantibody production, increased Tfh cell frequency, and impaired Treg cell regulation, in Ldlr-/- mice as compared with control T cells. In addition, we showed that dyslipidemia and Pbx1d-transgenic expression independently impaired the differentiation and function of Treg cells in vitro, suggesting a gene/environment additive effect. Thus, our results suggest that the combination of Pbx1d expression in T cells and dyslipidemia exacerbates both atherosclerosis and autoimmunity, at least in part through a dysregulation of Treg cell homeostasis.
