Metabolic regulation of immune responses.

The immune system defends against pathogens and maintains tissue homeostasis for the life of the organism. These diverse functions are bioenergetically expensive, requiring precise control of cellular metabolic pathways. Although initial observations in this area were made almost a century ago, studies over the past decade have elucidated the molecular basis for how extracellular signals control the uptake and catabolism of nutrients in quiescent and activated immune cells. Collectively, these studies have revealed that the metabolic pathways of oxidative metabolism, glycolysis, and glutaminolysis preferentially fuel the cell fate decisions and effector functions of immune cells. Here, we discuss these findings and provide a general framework for understanding how metabolism fuels and regulates the maturation of immune responses. A better understanding of the metabolic checkpoints that control these transitions might provide new insights for modulating immunity in infection, cancer, or inflammatory disorders.

Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance.

Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.

A thermogenic fat-epithelium cell axis regulates intestinal disease tolerance.

Disease tolerance, the capacity of tissues to withstand damage caused by a stimulus without a decline in host fitness, varies across tissues, environmental conditions, and physiologic states. While disease tolerance is a known strategy of host defense, its role in noninfectious diseases has been understudied. Here, we provide evidence that a thermogenic fat-epithelial cell axis regulates intestinal disease tolerance during experimental colitis. We find that intestinal disease tolerance is a metabolically expensive trait, whose expression is restricted to thermoneutral mice and is not transferable by the microbiota. Instead, disease tolerance is dependent on the adrenergic state of thermogenic adipocytes, which indirectly regulate tolerogenic responses in intestinal epithelial cells. Our work has identified an unexpected mechanism that controls intestinal disease tolerance with implications for colitogenic diseases.

TGF-ß1 limits the onset of innate lung inflammation by promoting mast cell-derived IL-6.

TGF-ß1 is an important suppressive mediator of inflammation, but it can also drive fibrosis and remodeling in the lung. In response to intratracheal LPS, neutrophils migrate into the lung, and TGF-ß1 was suggested to protect against the ensuing injury. However, the mechanisms for this protective role remain unknown. Using a model of acute lung injury, we demonstrate that TGF-ß1 decreases neutrophil numbers during the onset of injury. This was due to increased apoptosis rather than reduced migration. We demonstrate that TGF-ß1 does not directly regulate neutrophil apoptosis but instead functions through IL-6 to promote neutrophil clearance. rIL-6 is sufficient to promote neutrophil apoptosis and reduce neutrophilia in bronchoalveolar lavage fluid, while IL-6 increases rapidly following LPS-induced injury. Mast cells are a critical source of IL-6, because mast cell-deficient mice exhibit increased neutrophil numbers that are reduced by reconstitution with wild-type, but not IL-6(-/-), mast cells. Although IL-6 diminishes neutrophilia in mast cell-deficient mice, TGF-ß1 is ineffective, suggesting that these effects were mast cell dependent. Taken together, our findings establish a novel pathway through which TGF-ß1, likely derived from resident regulatory T cells, controls the severity and magnitude of early innate inflammation by promoting IL-6 from mast cells.

Regulatory T cells enhance mast cell production of IL-6 via surface-bound TGF-ß.

Mast cell degranulation is a hallmark of allergic reactions, but mast cells can also produce many cytokines that modulate immunity. Recently, CD25(+) regulatory T cells (Tregs) have been shown to inhibit mast cell degranulation and anaphylaxis, but their influence on cytokine production remained unknown. In this study, we show that, rather than inhibit, Tregs actually enhance mast cell production of IL-6. We demonstrate that, whereas inhibition of degranulation was OX40/OX40 ligand dependent, enhancement of IL-6 was due to TGF-ß. Interestingly, our data demonstrate that the Treg-derived TGF-ß was surface-bound, because the interaction was contact dependent, and no TGF-ß was detectable in the supernatant. Soluble TGF-ß1 alone was sufficient to enhance mast cell IL-6 production, and these supernatants were sufficient to promote Th17 skewing, but those from Treg-mast cell cultures were not, supporting this being surface-bound TGF-ß from the Tregs. Interestingly, the augmentation of IL-6 production occurred basally or in response to innate stimuli (LPS or peptidoglycan), adaptive stimuli (IgE cross-linking by specific Ag), and cytokine activation (IL-33). We demonstrate that TGF-ß led to enhanced transcription and de novo synthesis of IL-6 upon activation without affecting IL-6 storage or mRNA stability. In vivo, the adoptive transfer of Tregs inhibited mast cell-dependent anaphylaxis in a model of food allergy but promoted intestinal IL-6 and IL-17 production. Consequently, our findings establish that Tregs can exert divergent influences upon mast cells, inhibiting degranulation via OX40/OX40 ligand interactions while promoting IL-6 via TGF-ß.

Oncostatin M expression induced by bacterial triggers drives airway inflammatory and mucus secretion in severe asthma.

Exacerbations of symptoms represent an unmet need for people with asthma. Bacterial dysbiosis and opportunistic bacterial infections have been observed in, and may contribute to, more severe asthma. However, the molecular mechanisms driving these exacerbations remain unclear. We show here that bacterial lipopolysaccharide (LPS) induces oncostatin M (OSM) and that airway biopsies from patients with severe asthma present with an OSM-driven transcriptional profile. This profile correlates with activation of inflammatory and mucus-producing pathways. Using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that OSM is necessary and sufficient to drive pathophysiological features observed in severe asthma after exposure to LPS or Klebsiella pneumoniae. These findings were further supported through blockade of OSM with an OSM-specific antibody. Single-cell RNA sequencing from human lung biopsies identified macrophages as a source of OSM. Additional studies using Osm-deficient murine macrophages demonstrated that macrophage-derived OSM translates LPS signals into asthma-associated pathologies. Together, these data provide rationale for inhibiting OSM to prevent bacterial-associated progression and exacerbation of severe asthma.

Impairing oral tolerance promotes allergy and anaphylaxis: a new murine food allergy model.

BACKGROUND: Food allergy is a disorder in which antigenic food proteins elicit immune responses. Animal models of food allergy have several limitations that influence their utility, including failure to recapitulate several key immunologic hallmarks. Consequently, little is known regarding the pathogenesis and mechanisms leading to food allergy. Staphylococcus aureus-derived enterotoxins, a common cause of food contamination, are associated with antigen responses in atopic dermatitis. OBJECTIVE: We hypothesized that S aureus-derived enterotoxins might influence the development of food allergy. We examined the influence of administration of staphylococcal enterotoxin B (SEB) with food allergens on immunologic responses and compared these responses with those elicited by a cholera toxin-driven food allergy model. METHODS: Oral administration of ovalbumin or whole peanut extract with or without SEB was performed once weekly. After 8 weeks, mice were challenged with oral antigen alone, and the physiologic and immunologic responses to antigen were studied. RESULTS: SEB administered with antigen resulted in immune responses to the antigen. Responses were highly T(H)2 polarized, and oral challenge with antigen triggered anaphylaxis and local and systemic mast cell degranulation. SEB-driven sensitization induced eosinophilia in the blood and intestinal tissues not observed with cholera toxin sensitization. SEB impaired tolerance specifically by impairing expression of TGF-beta and regulatory T cells, and tolerance was restored with high-dose antigen. CONCLUSIONS: We demonstrate a new model of food allergy to oral antigen in common laboratory strains of mice that recapitulates many features of clinical food allergy that are not seen in other models. We demonstrate that SEB impairs oral tolerance and permits allergic responses.

Nutrient Sensing in CD11c Cells Alters the Gut Microbiota to Regulate Food Intake and Body Mass.

Microbial dysbiosis and inflammation are implicated in diet-induced obesity and insulin resistance. However, it is not known whether crosstalk between immunity and microbiota also regulates metabolic homeostasis in healthy animals. Here, we report that genetic deletion of tuberous sclerosis 1 (Tsc1) in CD11c+ myeloid cells (Tsc1f/fCD11cCre mice) reduced food intake and body mass in the absence of metabolic disease. Co-housing and fecal transplant experiments revealed a dominant role for the healthy gut microbiota in regulation of body weight. 16S rRNA sequencing, selective culture, and reconstitution experiments further confirmed that selective deficiency of Lactobacillus johnsonii Q1-7 contributed to decreased food intake and body mass in Tsc1f/fCD11cCre mice. Mechanistically, activation of mTORC1 signaling in CD11c cells regulated production of L. johnsonii Q1-7-specific IgA, allowing for its stable colonization in the gut. Together, our findings reveal an unexpected transkingdom immune-microbiota feedback loop for homeostatic regulation of food intake and body mass in mammals.

Warming the mouse to model human diseases.

Humans prefer to live within their thermal comfort or neutral zone, which they create by making shelters, wearing clothing and, more recently, by regulating their ambient temperature. These strategies enable humans to maintain a constant core temperature (a trait that is conserved across all endotherms, including mammals and birds) with minimal energy expenditure. Although this primordial drive leads us to seek thermal comfort, we house our experimental animals, laboratory mice (Mus musculus), under conditions of thermal stress. In this Review, we discuss how housing mice below their thermoneutral zone limits our ability to model and study human diseases. Using examples from cardiovascular physiology, metabolic disorders, infections and tumour immunology, we show that certain phenotypes observed under conditions of thermal stress disappear when mice are housed at thermoneutrality, whereas others emerge that are more consistent with human biology. Thus, we propose that warming the mouse might enable more predictive modelling of human diseases and therapies.

Adipocyte JAK2 mediates growth hormone-induced hepatic insulin resistance.

For nearly 100 years, growth hormone (GH) has been known to affect insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here, we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extrahepatic, adipose tissue-dependent mechanism.

Thermoneutral Housing Accelerates Metabolic Inflammation to Potentiate Atherosclerosis but Not Insulin Resistance.

Chronic, low-grade inflammation triggered by excess intake of dietary lipids has been proposed to contribute to the pathogenesis of metabolic disorders, such as obesity, insulin resistance, type 2 diabetes, and atherosclerosis. Although considerable evidence supports a causal association between inflammation and metabolic diseases, most tests of this link have been performed in cold-stressed mice that are housed below their thermoneutral zone. We report here that thermoneutral housing of mice has a profound effect on the development of metabolic inflammation, insulin resistance, and atherosclerosis. Mice housed at thermoneutrality develop metabolic inflammation in adipose tissue and in the vasculature at an accelerated rate. Unexpectedly, this increased inflammatory response contributes to the progression of atherosclerosis but not insulin resistance. These findings not only suggest that metabolic inflammation can be uncoupled from obesity-associated insulin resistance, but also point to how thermal stress might limit our ability to faithfully model human diseases in mice.

Hypothalamic inflammation and the central nervous system control of energy homeostasis.

The control of energy homeostasis relies on robust neuronal circuits that regulate food intake and energy expenditure. Although the physiology of these circuits is well understood, the molecular and cellular response of this program to chronic diseases is still largely unclear. Hypothalamic inflammation has emerged as a major driver of energy homeostasis dysfunction in both obesity and anorexia. Importantly, this inflammation disrupts the action of metabolic signals promoting anabolism or supporting catabolism. In this review, we address the evidence that favors hypothalamic inflammation as a factor that resets energy homeostasis in pathological states.

Adipose tissue macrophages: Amicus adipem?

Chronic overnutrition drives complex adaptations within both professional metabolic and bystander tissues that, despite intense investigation, are still poorly understood. Xu et al. (2013) now describe the unexpected ability of adipose tissue macrophages to buffer lipids released from obese adipocytes in a manner independent of inflammatory macrophage activation.