Administration of soluble gp130Fc disrupts M-1 macrophage polarization, dendritic cell activation, MDSC expansion and Th-17 induction during experimental cerebral malaria.

Regulatory effect of IL-6 on various immune cells plays a crucial role during experimental cerebral malaria pathogenesis. IL-6 neutralization can restore distorted ratios of myeloid dendritic cells and plasmacytoid dendritic cells as well as the balance between Th-17 and T-regulatory cells. IL-6 can also influence immune cells through classical and trans IL-6 signalling pathways. As trans IL-6 signalling is reportedly involved during malaria pathogenesis, we focused on studying the effects of trans IL-6 signalling blockade on various immune cell populations and how they regulate ECM progression. Results show that administration of sgp130Fc recombinant chimera protein lowers the parasitemia, increases the survivability of Plasmodium berghei ANKA infected mice, and restores the distorted ratios of M1/M2 macrophage, mDC/pDC, and Th-17/Treg. IL-6 trans signalling blockade has been found to affect both expansion of myeloid derived suppressor cells (MDSCs) and expression of inflammatory markers on them during Plasmodium berghei ANKA infection indicating that trans IL-6 signalling might regulate various immune cells and their function during ECM. In this work for the first time, we delineate the effect of sgp130Fc administration on influencing the immunological changes within the host secondary lymphoid organ during ECM induced by Plasmodium berghei ANKA infection.

AMPK activator AICAR in combination with anti-mouse IL10 mAb restores the functionality of intra-tumoral Tfh cells in the 4T1 mouse model.

4T1 cell-mediated TNBC breast cell carcinoma is a highly malignant mice tumor model which resembles an advanced stage of breast cancer in humans. Tumor progression occurs depending on the intra-tumoral balance of pro- and anti- tumorigenic immune cells. Enhancement of T-cell-mediated anti-tumor immunity will be advantageous for inhibiting tumor progression and improving the efficacy of cancer therapy. This study is focused on alleviating suppressed anti-tumor immune response by improving CD4+ T follicular helper cell (Tfh) response in 4T1 mice. We employed anti-IL10 mAb along with metabolic drugs 2-deoxy-D-glucose (2DG) which inhibits the glycolytic pathway and Cpt1a inhibitor Etomoxir which inhibits FAO. AMPK activator AICAR with or without anti-IL10 mAb was also used to ameliorate metabolic stress and exhaustion faced by immune cells. Our results demonstrate that synergistic treatment with 2DG/Etomoxir + anti-IL10 mAb induced Tfh cell, memory B, and GC B cell response more potently compared to treatment with 2DG or Etomoxir treatment alone as observed in several LNs and tumor tissue of 4T1 mouse. However, AICAR + anti-IL10 mAb increased the frequency of intratumoral Tfh cells, simultaneously downregulated Tfr cells; and improved humoral response by stimulating upregulation of memory B, GC B, and plasmablasts in tumor-draining, axillary, and mesenteric LNs of 4T1 mouse.

Regulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets.

Metabolism is a dynamic process and keeps changing from time to time according to the demand of a particular cell to meet its bio-energetic requirement. Different immune cells rely on distinct metabolic programs which allow the cell to balance its requirements for energy, molecular biosynthesis, and effector activity. In the aspect of infection and cancer immunology, effector T and B cells get exhausted and help tumor cells to evade immunosurveillance. On the other hand, T cells become hyperresponsive in the scenario of autoimmune diseases. In this article, we have explored the uniqueness and distinct metabolic features of key CD4+ T and B helper cell subsets, CD4+ T, B regulatory cell subsets and CD8+ T cells regarding health and disease. Th1 cells rely on glycolysis and glutaminolysis; inhibition of these metabolic pathways promotes Th1 cells in Treg population. However, Th2 cells are also dependent on glycolysis but an abundance of lactate within TME shifts their metabolic dependency to fatty acid metabolism. Th17 cells depend on HIF-1α mediated glycolysis, ablation of HIF-1α reduces Th17 cells but enhance Treg population. In contrast to effector T cells which are largely dependent on glycolysis for their differentiation and function, Treg cells mainly rely on FAO for their function. Therefore, it is of utmost importance to understand the metabolic fates of immune cells and how it facilitates their differentiation and function for different disease models. Targeting metabolic pathways to restore the functionality of immune cells in diseased conditions can lead to potent therapeutic measures.

Heterodimer formation by Oct4 and Smad3 differentially regulates epithelial-to-mesenchymal transition-associated factors in breast cancer progression.

The multifunctional cytokine TGF-ß crucially participates in breast cancer (BCa) metastasis and works differently in the disease stages, thus contributing in BCa progression. We address connections between TGF-ß and the stem cell-related transcription factor (TF) Oct4 in BCa. In 147 BCa patients with infiltrating duct carcinoma, we identified a significantly higher number of cases with both moderate/high Oct4 expression and high TGF-ß in late stages compared to early stages of the disease. In vitro studies showed that TGF-ß elevated Oct4 expression, which in turn, regulated Epithelial-to-Mesenchymal transition (EMT)-regulatory gene (Snail and Slug) expression, migratory ability, chemotactic invasiveness and extracellular matrix (ECM) degradation potential of BCa cells. Putative binding sites for Oct4 on the snail, slug and cxcl13 promoters and for Smad3 on the snail and slug promoters were identified. Promoter activities of snail and slug were greater in dual-treated cells than only TGF-ß-treated or Oct4-overexpressing cells. CXCL13 mRNA fold changes, however, were low in cells induced with TGF-ß, compared to dual-treated or Oct4-overexpressing cells. Our co-IP studies confirmed that Oct4 and Smad3 form heterodimers that recognize specific promoter sequences to promote Snail and Slug expression, but which in turn, indirectly inhibits Smad3-mediated repression of CXCL13 expression, allowing Oct4 to act as a positive TF for CXCL13. Taken together, these data suggest that TGF-ß signaling and Oct4 cooperate to induce expression of EMT-related genes Snail, Slug and CXCL13, which accelerates disease progression, particularly in the late stages, and may indicate a poor prognosis for BCa patients.