Metabolic regulation and function of T helper cells in neuroinflammation.

Neuroinflammatory conditions such as multiple sclerosis (MS) are initiated by pathogenic immune cells invading the central nervous system (CNS). Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in MS and in other neuroinflammatory autoimmune diseases including animal models that have been developed for MS. T helper cells are classically categorized into different subsets, but heterogeneity exists within these subsets. Untangling the more complex regulation of these subsets will clarify their functional roles in neuroinflammation. Here, we will discuss how differentiation, immune checkpoint pathways, transcriptional regulation and metabolic factors determine the function of CD4+ T cell subsets in CNS autoimmunity. T cells rely on metabolic reprogramming for their activation and proliferation to meet bioenergetic demands. This includes changes in glycolysis, glutamine metabolism and polyamine metabolism. Importantly, these pathways were recently also implicated in the fine tuning of T cell fate decisions during neuroinflammation. A particular focus of this review will be on the Th17/Treg balance and intra-subset functional states that can either promote or dampen autoimmune responses in the CNS and thus affect disease outcome. An increased understanding of factors that could tip CD4+ T cell subsets and populations towards an anti-inflammatory phenotype will be critical to better understand neuroinflammatory diseases and pave the way for novel treatment paradigms.

Comparative multi-tissue profiling reveals extensive tissue-specificity in transcriptome reprogramming during thermal adaptation.

Thermal adaptation is an extensively used intervention for enhancing or suppressing thermogenic and mitochondrial activity in adipose tissues. As such, it has been suggested as a potential lifestyle intervention for body weight maintenance. While the metabolic consequences of thermal acclimation are not limited to the adipose tissues, the impact on the rest of the tissues in context of their gene expression profile remains unclear. Here, we provide a systematic characterization of the effects in a comparative multi-tissue RNA sequencing approach following exposure of mice to 10 °C, 22 °C, or 34 °C in a panel of organs consisting of spleen, bone marrow, spinal cord, brain, hypothalamus, ileum, liver, quadriceps, subcutaneous-, visceral- and brown adipose tissues. We highlight that transcriptional responses to temperature alterations exhibit a high degree of tissue-specificity both at the gene level and at GO enrichment gene sets, and show that the tissue-specificity is not directed by the distinct basic gene expression pattern exhibited by the various organs. Our study places the adaptation of individual tissues to different temperatures in a whole-organism framework and provides integrative transcriptional analysis necessary for understanding the temperature-mediated biological programming.

Humans, mice and most other mammals are constantly exposed to fluctuations in the temperature of their environment. These fluctuations cause striking metabolic effects in the body, for example, exposure to cold promotes burning of calories to generate heat, thereby reducing how much fat accumulates in the body. On the other hand, warmer temperatures strengthen the bones and protect against a bone disease known as osteoporosis. As such, it has been suggested that exposure to alternating warm or cold temperatures could be a potential lifestyle intervention that conveys various benefits to our health. Our body stores fat in tissues known as adipose tissues, which are found all over the body including under the skin and around our major organs and muscles. Exposure to cold triggers changes in the activities of some genes in the adipose tissues to burn more calories. But it remains unclear how temperature affects the activities of other organs with respect to their expression of genes in the whole-body context. Hadadi, Spiljar et al. used an RNA sequencing approach to study the activities of genes in various tissues of mice exposed to cold (10°C), room temperature (22°C), or mild warm (34°C). The experiments revealed numerous genes whose levels were different in the various organs and temperatures tested. Overall, adipose tissues experienced the biggest changes in gene levels between different temperatures, followed by tissues involved in immune responses, and the brain and spinal cord tissues. Each organ changed gene expression levels in its own way. , and this was not due to the different intimate gene expression profile between the various organs. These findings improve our understanding of how changes in temperature affect mammals by putting the responses of individual tissues into the context of the whole body. Hadadi, Spiljar et al. also generated a web-based, free-to-use application to allow others to view and further analyze the data collected in this work for gene levels in the various organs of interest.

Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα.

Intestinal surface changes in size and function, but what propels these alterations and what are their metabolic consequences is unknown. Here we report that the food amount is a positive determinant of the gut surface area contributing to an increased absorptive function, reversible by reducing daily food. While several upregulated intestinal energetic pathways are dispensable, the intestinal PPARα is instead necessary for the genetic and environment overeating-induced increase of the gut absorptive capacity. In presence of dietary lipids, intestinal PPARα knock-out or its pharmacological antagonism suppress intestinal crypt expansion and shorten villi in mice and in human intestinal biopsies, diminishing the postprandial triglyceride transport and nutrient uptake. Intestinal PPARα ablation limits systemic lipid absorption and restricts lipid droplet expansion and PLIN2 levels, critical for droplet formation. This improves the lipid metabolism, and reduces body adiposity and liver steatosis, suggesting an alternative target for treating obesity.

Metataxonomic and Metabolic Impact of Fecal Microbiota Transplantation From Patients With Pancreatic Cancer Into Germ-Free Mice: A Pilot Study.

Background: Body weight (BW) loss is prevalent in patients with pancreatic cancer (PC). Gut microbiota affects BW and is known to directly shape the host immune responses and antitumor immunity. This pilot study evaluated the link between gut microbiota, metabolic parameters and inflammatory/immune parameters, through the fecal material transplantation (FMT) of PC patients and healthy volunteers into germ-free (GF) mice. Methods: We transplanted the feces from five PC patients and five age- and gender-matched healthy volunteers into two GF mice each. Mouse BW and energy intake were measured every 1-5 days, oral glucose on day 21, insulin tolerance on day 26, fecal bacterial taxonomic profile by 16S rRNA gene sequencing on day 5, 10, 15 and 30, and gut-associated lymphoid tissue T cells, plasma cytokines and weights of fat and muscle mass at sacrifice (day 34). Results are presented as mean ± SD. The continuous parameters of mice groups were compared by linear univariate regressions, and their bacterial communities by Principal Coordinates Analysis (PCoA), Bray-Curtis similarity and ANCOM test. Results: Recipients of feces from PC patients and healthy volunteers had similar BW gain and food intake. Visceral fat was lower in recipients of feces from PC patients than from healthy individuals (0.72 ± 0.17 vs. 0.92 ± 0.14 g; coeff -0.19, 95% CI -0.38, -0.02, p=0.035). The other non-metataxonomic parameters did not differ between groups. In PCoA, microbiota from PC patients clustered apart from those of healthy volunteers and the same pattern was observed in transplanted mice. The proportions of Clostridium bolteae, Clostridium scindens, Clostridium_g24_unclassified and Phascolarctobacterium faecium were higher, while those of Alistipes obesi, Lachnospiraceae PAC000196_s and Coriobacteriaceae_unclassified species were lower in PC patients and in mice transplanted with the feces from these patients. Conclusion: In this pilot study, FMT from PC patients was associated with a decrease in visceral fat as compared to FMT from healthy individuals. Some of the differences in fecal microbiota between PC and control samples are common to humans and mice. Further research is required to confirm that feces contain elements involved in metabolic and immune alterations.

Cold exposure protects from neuroinflammation through immunologic reprogramming.

Autoimmunity is energetically costly, but the impact of a metabolically active state on immunity and immune-mediated diseases is unclear. Ly6Chi monocytes are key effectors in CNS autoimmunity with an elusive role in priming naive autoreactive T cells. Here, we provide unbiased analysis of the immune changes in various compartments during cold exposure and show that this energetically costly stimulus markedly ameliorates active experimental autoimmune encephalomyelitis (EAE). Cold exposure decreases MHCII on monocytes at steady state and in various inflammatory mouse models and suppresses T cell priming and pathogenicity through the modulation of monocytes. Genetic or antibody-mediated monocyte depletion or adoptive transfer of Th1- or Th17-polarized cells for EAE abolishes the cold-induced effects on T cells or EAE, respectively. These findings provide a mechanistic link between environmental temperature and neuroinflammation and suggest competition between cold-induced metabolic adaptations and autoimmunity as energetic trade-off beneficial for the immune-mediated diseases.

Warmth Prevents Bone Loss Through the Gut Microbiota.

Osteoporosis is the most prevalent metabolic bone disease, characterized by low bone mass and microarchitectural deterioration. Here, we show that warmth exposure (34°C) protects against ovariectomy-induced bone loss by increasing trabecular bone volume, connectivity density, and thickness, leading to improved biomechanical bone strength in adult female, as well as in young male mice. Transplantation of the warm-adapted microbiota phenocopies the warmth-induced bone effects. Both warmth and warm microbiota transplantation revert the ovariectomy-induced transcriptomics changes of the tibia and increase periosteal bone formation. Combinatorial metagenomics/metabolomics analysis shows that warmth enhances bacterial polyamine biosynthesis, resulting in higher total polyamine levels in vivo. Spermine and spermidine supplementation increases bone strength, while inhibiting polyamine biosynthesis in vivo limits the beneficial warmth effects on the bone. Our data suggest warmth exposure as a potential treatment option for osteoporosis while providing a mechanistic framework for its benefits in bone disease.

The Immune System Bridges the Gut Microbiota with Systemic Energy Homeostasis: Focus on TLRs, Mucosal Barrier, and SCFAs.

The gut microbiota is essential for the development and regulation of the immune system and the metabolism of the host. Germ-free animals have altered immunity with increased susceptibility to immunologic diseases and show metabolic alterations. Here, we focus on two of the major immune-mediated microbiota-influenced components that signal far beyond their local environment. First, the activation or suppression of the toll-like receptors (TLRs) by microbial signals can dictate the tone of the immune response, and they are implicated in regulation of the energy homeostasis. Second, we discuss the intestinal mucosal surface is an immunologic component that protects the host from pathogenic invasion, is tightly regulated with regard to its permeability and can influence the systemic energy balance. The short chain fatty acids are a group of molecules that can both modulate the intestinal barrier and escape the gut to influence systemic health. As modulators of the immune response, the microbiota-derived signals influence functions of distant organs and can change susceptibility to metabolic diseases.

Chemoradiation Increases PD-L1 Expression in Certain Melanoma and Glioblastoma Cells.

Immunotherapy approaches currently make their way into the clinics to improve the outcome of standard radiochemotherapy (RCT). The programed cell death receptor ligand 1 (PD-L1) is one possible target that, upon blockade, allows T cell-dependent antitumor immune responses to be executed. To date, it is unclear which RCT protocol and which fractionation scheme leads to increased PD-L1 expression and thereby renders blockade of this immune suppressive pathway reasonable. We therefore investigated the impact of radiotherapy (RT), chemotherapy (CT), and RCT on PD-L1 surface expression on tumor cells of tumor entities with differing somatic mutation prevalence. Murine melanoma (B16-F10), glioblastoma (GL261-luc2), and colorectal (CT26) tumor cells were treated with dacarbazine, temozolomide, and a combination of irinotecan, oxaliplatin, and fluorouracil, respectively. Additionally, they were irradiated with a single dose [10 Gray (Gy)] or hypo-fractionated (2 × 5 Gy), respectively, norm-fractionated (5 × 2 Gy) radiation protocols were used. PD-L1 surface and intracellular interferon (IFN)-gamma expression was measured by flow cytometry, and IL-6 release was determined by ELISA. Furthermore, tumor cell death was monitored by AnnexinV-FITC/7-AAD staining. For first in vivo analyses, the B16-F10 mouse melanoma model was chosen. In B16-F10 and GL261-luc2 cells, particularly norm-fractionated and hypo-fractionated radiation led to a significant increase of surface PD-L1, which could not be observed in CT26 cells. Furthermore, PD-L1 expression is more pronounced on vital tumor cells and goes along with increased levels of IFN-gamma in the tumor cells. In melanoma cells CT was the main trigger for IL-6 release, while in glioblastoma cells it was norm-fractionated RT. In vivo, fractionated RT only in combination with dacarbazine induced PD-L1 expression on melanoma cells. Our results suggest a tumor cell-mediated upregulation of PD-L1 expression following in particular chemoradiation that is not only dependent on the somatic mutation prevalence of the tumor entity.