Antigen-presenting innate lymphoid cells orchestrate neuroinflammation.

Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases1-6, but the pathways that control these responses remain unclear. Here we define a population of inflammatory group 3 innate lymphoid cells (ILC3s) that infiltrate the CNS in a mouse model of multiple sclerosis. These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS, function as antigen-presenting cells that restimulate myelin-specific T cells, and are increased in individuals with multiple sclerosis. Notably, antigen presentation by inflammatory ILC3s is required to promote T cell responses in the CNS and the development of multiple-sclerosis-like disease in mouse models. By contrast, conventional and tissue-resident ILC3s in the periphery do not appear to contribute to disease induction, but instead limit autoimmune T cell responses and prevent multiple-sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data define a population of inflammatory ILC3s that is essential for directly promoting T-cell-dependent neuroinflammation in the CNS and reveal the potential of harnessing peripheral tissue-resident ILC3s for the prevention of autoimmune disease.

IL-17 controls central nervous system autoimmunity through the intestinal microbiome.

Interleukin-17A- (IL-17A) and IL-17F-producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.

Expression of IL-17F is associated with non-pathogenic Th17 cells.

IL-17A and IL-17F share the highest sequence homology of the IL-17 family and signal via the same IL-17RA/RC receptor heterodimer. To better explore the expression of these two cytokines, we used a double reporter mouse strain (IL-17DR mice), where IL-17A expressing cells are marked by enhanced green fluorescent protein (eGFP) while red fluorescence protein (RFP) reports the expression of IL-17F. In steady state, we found that Th17 and γδ T cells only expressed IL-17A, while IL-17F expression was restricted to CD8 T cells (Tc17) and innate lymphoid cells (ILC type 3) of the gut. In experimental autoimmune encephalomyelitis, the vast majority of CNS-infiltrating Th17 cells expressed IL-17A but not IL-17F. In contrast, anti-CD3-induced, TGF-ß-driven Th17 cells in the gut expressed both of these IL-17 cytokines. In line with this, in vitro differentiation of Th17 cells in the presence of IL-1ß led primarily to IL-17A expressing T cells, while TGF-ß induced IL-17F co-expressing Th17 cells. Our results suggest that expression of IL-17F is associated with non-pathogenic T cells, pointing to a differential function of IL-17A versus IL-17F. KEY MESSAGES: Naïve mice: CD4+ T cells and γδ T cells express IL-17A, and Tc17 cells express IL-17F. Gut ILC3 show differential expression of IL17A and F. Th17 differentiation with TGF-ß1 induces IL-17A and F, whereas IL-1ß induced cells expressing IL-17A. Th17 cells in EAE in CNS express IL-17A only. Gut Th17 cells induced by anti-CD3 express IL-17A and F together as skin γδ T cells of IMQ-treated mice.

MiR-126 Regulates Growth Factor Activities and Vulnerability to Toxic Insult in Neurons.

Dysfunction of growth factor (GF) activities contributes to the decline and death of neurons during aging and in neurodegenerative diseases. In addition, neurons become more resistant to GF signaling with age. Micro (mi)RNAs are posttranscriptional regulators of gene expression that may be crucial to age- and disease-related changes in GF functions. MiR-126 is involved in regulating insulin/IGF-1/phosphatidylinositol-3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling, and we recently demonstrated a functional role of miR-126 in dopamine neuronal cell survival in models of Parkinson's disease (PD)-associated toxicity. Here, we show that elevated levels of miR-126 increase neuronal vulnerability to ubiquitous toxicity mediated by staurosporine (STS) or Alzheimer's disease (AD)-associated amyloid beta 1-42 peptides (Aß1-42). The neuroprotective factors IGF-1, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and soluble amyloid precursor protein α (sAPPα) could diminish but not abrogate the toxic effects of miR-126. In miR-126 overexpressing neurons derived from Tg6799 familial AD model mice, we observed an increase in Aß1-42 toxicity, but surprisingly, both Aß1-42 and miR-126 promoted neurite sprouting. Pathway analysis revealed that miR-126 overexpression downregulated elements in the GF/PI3K/AKT and ERK signaling cascades, including AKT, GSK-3ß, ERK, their phosphorylation, and the miR-126 targets IRS-1 and PIK3R2. Finally, inhibition of miR-126 was neuroprotective against both STS and Aß1-42 toxicity. Our data provide evidence for a novel mechanism of regulating GF/PI3K signaling in neurons by miR-126 and suggest that miR-126 may be an important mechanistic link between metabolic dysfunction and neurotoxicity in general, during aging, and in the pathogenesis of specific neurological disorders, including PD and AD.