Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF–expressing) and anti-inflammatory (IL-10–expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a “fourth signal” that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

Autophagy plays a complicated role in tumorigenesis, and the effects of autophagy in drug resistance have not been fully known. The aim of this study was to evaluate autophagy activity in lung cancer cells derived from different origins and explore the mechanism regulating autophagy in tyrosine kinase inhibitor (TKI) resistance. We found basal level of autophagy had no significant increase in resistant H1650 and H1975 cells compared with sensitive HCC827 and PC9 cells. After erlotinib treatment, the autophagy activity enhanced threefold in H1650 cells but a little in H1975 cells. Inhibiting autophagy with 3-MA increased apoptosis in H1650 rather than H1975 cells. Combined with transmission microscope, results showed PC9 cells tended to be apoptotic and more autophagosomes formed in H1650 cells, which may be correlated with cell viability. GATA6 expression was found markedly elevated in H1650 cells after erlotinib and knocking down GATA6 led to significantly reduced autophagy activity and cell viability. Furthermore, a significant increase of GATA6 and LC3-II expression was observed in insensitive tissues compared with sensitive ones by immunostaining in nonsmall cell lung cancer (NSCLC) patients. With chi-square test, we found GATA6 was positively correlated with LC3-II. The Kaplan-Meier curve analyses further showed patients with high GATA6 had lower overall survival and progression-free survival rates than those with low GATA6 after EGFR-TKI treatment. Our results suggest that GATA6 could enhance autophagy activity contributing to TKI resistance. Targeting GATA6 and autophagy together with TKI may be promising to overcome drug resistance in NSCLC.

Multiple sclerosis (MS) is a neurodegenerative and demyelinating autoimmune disease mediated by autoreactive T cells that affects the central nervous system (CNS). Electroacupuncture (EA) has emerged as an alternative or supplemental treatment for MS, but the mechanism by which EA may alleviate MS symptoms is unresolved. Here, we examined the effects of EA at the Zusanli (ST36) acupoint on mice with experimental autoimmune encephalomyelitis (EAE), the predominant animal model of MS. The effects of EA on EAE emergence, inflammatory cell levels, proinflammatory cytokines, and spinal cord pathology were examined. EA treatment attenuated the EAE clinical score and associated spinal cord demyelination, while reducing the presence of proinflammatory cytokines in mononuclear cells (MNCs), downregulating microRNA (miR)-155, and upregulating the opioid peptide precursor proopiomelanocortin (POMC) in the CNS. Experiments in which cultured neurons were transfected with a miR-155 mimic or a miR-155 inhibitor further showed that the direct modulation of miR-155 levels could regulate POMC levels in neurons. In conclusion, the alleviation of EAE by EA is characterized by reduced proportions of Th1/Th17 cells and increased proportions of Th2 cells, POMC upregulation, and miR-155 downregulation, while miR-155 itself can suppress POMC expression. These results, support the hypothesis that the effects of EA on EAE may involve the downregulation of miR-155.

MicroRNA 182 is important for the clonal expansion of CD4⁺ T cells (Th) following IL‐2 stimulation and is a potential therapeutic target for autoimmune diseases. In the present study, we investigated the role of microRNA 182 in the differentiation of pro‐inflammatory CD4⁺ T helper cell by overexpressing or silencing microRNA 182 expression both in in vivo and in vitro settings. We report that in the studied Chinese cohort, microRNA 182 is upregulated in patients with relapse and remitting multiple sclerosis (RRMS) and this upregulation is associated with increased IFN‐γ producing CD4⁺ Th1 cells in the circulation. In the murine experimental autoimmune encephalomyelitis (EAE) model, global microRNA 182 overexpression exacerbates clinical symptoms and results in augmented CD4⁺IFN‐γ⁺ Th1 and CD4⁺IL‐17⁺ Th17 differentiation in vivo. Addition of microRNA 182 mimics in vitro represses both the protein expression and transcriptional activity of hypoxia induced factor 1α (HIF‐1α) but increases the level of IFN‐γ transcripts in sorted murine CD4⁺ T cells. Together, our results provide evidence that microRNA 182 may be one of the transitional hubs contribution to regulate Th cells expansion in response to self‐antigens and differentiation of antigen specific Th cells during the progression of autoimmune inflammations.