Dataset Information

EB1-3 Chain of IL-35 Along With TGF-? Synergistically Regulate Anti-leishmanial Immunity.

ABSTRACT: Immunosuppression is a characteristic feature of chronic leishmaniasis. The dynamicity and the functional cross talks of host immune responses during Leishmania infection are still not clearly understood. Here we explored the functional aspects of accumulation of immune suppressive cellular and cytokine milieu during the progression of murine visceral leishmaniasis. In addition to IL-10 and TGF-?, investigation on the responses of different subunit chains of IL-12 family revealed a progressive elevation of EBI-3 and p35 chains of EBI-3 with Leishmania donovani infection in BALB/c mice. The expansion of CD25 and FoxP3 positive T cells is associated with loss of IFN-? and TNF-? response in advanced disease. Ex-vivo and in vivo neutralization of TGF-? and EBI-3 suggests a synergism in suppression of host anti-leishmanial immunity. The down-regulation of EBI-3 and TGF-? is crucial for re-activation of JAK-STAT pathway for induction as well as restoration of protective immunity against L. donovani infection.

SUBMITTER: Asad M

PROVIDER: S-EPMC6474326 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

EB1-3 Chain of IL-35 Along With TGF-β Synergistically Regulate Anti-leishmanial Immunity.

Asad Mohammad M Sabur Abdus A Shadab Mohammad M Das Sonali S Kamran Mohd M Didwania Nicky N Ali Nahid N

Frontiers in immunology 20190412

Immunosuppression is a characteristic feature of chronic leishmaniasis. The dynamicity and the functional cross talks of host immune responses during <i>Leishmania</i> infection are still not clearly understood. Here we explored the functional aspects of accumulation of immune suppressive cellular and cytokine milieu during the progression of murine visceral leishmaniasis. In addition to IL-10 and TGF-β, investigation on the responses of different subunit chains of IL-12 family revealed a progre ...[more]

PMID: 31031744

Similar Datasets

Project description:BACKGROUND:Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson's disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS:Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS:We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS:These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

Project description:Inhibitory cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), are humoral factors involved in the suppressive function of regulatory T cells and play critical roles in maintaining immune homeostasis. However, TGF-β and IL-10 also have pleiotropic effects and induce humoral immune responses depending on conditions, and thus their therapeutic application to autoimmune diseases remains limited. Here, we show that a combination of TGF-β and IL-10, but not single cytokine, is required to suppress B cell activation induced by toll-like receptor (TLR) stimulation. In in vivo analyses, the simultaneous presence of TGF-β and IL-10 effectively suppressed TLR-mediated antigen-specific immune responses and ameliorated pathologies in imiquimod (TLR7 agonist)-induced lupus model and lupus-prone MRL/lpr mice. Intriguingly, TGF-β and IL-10 synergistically modulated transcriptional programs and suppressed cellular energetics of both glycolysis and oxidative phosphorylation via inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/S6 kinase 1 (S6K1) pathway in TLR-stimulated B cells. On the other hand, enhancement of mTOR signaling and mitochondrial biosynthesis in TLR-stimulated B cells counteracted the synergistic inhibitory effects. The inhibitory cytokine synergy of TGF-β and IL-10 via suppression of energy metabolism was also observed in human TLR-stimulated B cells. There is increasing evidence supporting the importance of adequate metabolic signals in various immune cells to exert their immune function. In this study, we have shown that a previously unrecognized synergy of inhibitory cytokines regulates systemic humoral immune responses via modulating immunometabolism in B cells. Our findings indicate that inhibition of B cell metabolism mediated by two synergistic cytokines contributes to the induction of immune tolerance and could be a new therapeutic strategy for autoimmune diseases such as systemic lupus erythematosus.

Project description:Periodontitis is one of the most prevalent chronic inflammatory diseases and is induced by the interaction between oral microorganisms and the host immune system. Plasma cells are of special interest in chronic periodontitis (CP), as they represent ~50% of infiltrated immune cells in periodontal lesions. Plasma cells constitute the only known cell type capable of antibody production; however, recent evidence supports an emerging role for distinct sets of plasma cells in cytokine production. However, the presence of cytokine-producing plasma cells in CP is unknown. In this study, we used immunohistochemistry to detect significantly elevated levels of IL-35 and IL-37 (2 recently identified anti-inflammatory cytokines) in CP gingival tissue as compared with healthy tissue. Remarkably, we demonstrate that CD138+ CD38+ plasma cells are the major immune cell type in CP gingival tissues and that these cells produce IL-35 and IL-37. We used immunofluorescence and confocal microscopy analysis to identify a subset of plasma cells with robust cytoplasmic expression of IL-37-we denote this subset as IL-37-producing plasma cells (CD138+CD38+PIL-37). Another subset of plasma cells coproduces IL-35 and IL-37 and is denoted as IL-37/IL-35-coproducing plasma cells (CD138+CD38+PIL-35/IL-37). We determined that these 2 plasma cell subsets are IgG+plasma cells. Moreover, we show that human recombinant IL-35 and IL-37 exhibit a dose-dependent inhibition of osteoclast formation in vitro (~78.9% and 97.7% inhibition in 300 ng/mL of IL-35 and IL-37, respectively, P < 0.05). Overall, our findings suggest that PIL-37 and PIL-35/IL-37 exist as subsets of plasma cells in CP lesions and that these 2 new types of plasma cells may regulate periodontitis pathogenesis by inhibiting alveolar bone loss through directly blocking osteoclast formation. Importantly, these data suggest a novel role of plasma cells and offer potential new mechanistic and regulatory targets to be investigated in the context of periodontal health and disease.

Dataset Information

EB1-3 Chain of IL-35 Along With TGF-? Synergistically Regulate Anti-leishmanial Immunity.

Publications

EB1-3 Chain of IL-35 Along With TGF-β Synergistically Regulate Anti-leishmanial Immunity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets