Immune cell metabolism in autoimmunity

Immune metabolism is a rapidly moving field. While most of the research has been conducted to define the metabolism of healthy immune cells in the mouse, it is recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities, as well as a means to understand the fundamental mechanisms of autoimmune activation more clearly. Here, we review recent publications that have reported how the major metabolic pathways are affected in autoimmune diseases, with a focus on rheumatic diseases.     

Adipose tissue at the nexus of systemic and cellular immunometabolism

At the simplest interpretation of the word, Immunometabolism describes the intersection of the fields of immunology and metabolism. With rapidly growing interest in this field, the term has expanded, and now encompasses a variety of concepts and definitions shaped by an individual’s scientific area of expertise, cell-type and tissue of interest, and biological approach. One scientist may be interested in investigating the intrinsic metabolic checkpoints that drive a M1 versus M2 macrophage response, while another may be interested in how macrophages affect systemic metabolism during obesity. Although both interests have very different foci, they both reflect the current interests in immunometabolism and studies over the last decade have uncovered new metabolic nodes that dictate the course of effector fate within cells, as well as an unexpected role for the immune system in controlling systemic metabolism. Thus, immunometabolism is at the frontier for many novel therapeutic targets to control both cell intrinsic and whole body metabolism in many diseases including cancer, diabetes, obesity, and sepsis among others. In this review, we hope to break down the word immunometabolism into two main themes: whole-body metabolism and cellular bioenergetics. In each instance we will focus on the adipose tissue and its resident immune cells to illustrate recent advances in both sectors of immunometabolism.     

Vitamin D in Systemic and Organ-Specific Autoimmune Diseases

Lately, vitamin D has been linked with metabolic and immunological processes, which established its role as an essential component of human health preservation. Vitamin D has been defined as natural immune modulators, and upon activation of its receptors (VDRs), it regulates calcium metabolism, cellular growth, proliferation and apoptosis, and other immunological functions. Epidemiological data underline a strong correlation between poor vitamin D status and higher risk for chronic inflammatory illnesses of various etiologies, including autoimmune diseases. Epidemiological, genetic, and basic studies indicated a potential role of vitamin D in the pathogenesis of certain systemic and organ-specific autoimmune diseases. These studies demonstrate correlation between low vitamin D and prevalence of diseases. In addition, VDRs’ polymorphisms observed in some of these autoimmune diseases may further support a plausible pathogenic link. Notably, for some autoimmune disease, no correlation with vitamin D levels could be confirmed. Thus, in the current review we present the body of evidence regarding the plausible roles of vitamin D and VDR’s polymorphism in the pathogenesis of autoimmunity. We summarize the data regarding systemic (i.e., systemic lupus erythematosus, rheumatoid arthritis, etc.) and organ-specific (i.e., multiple sclerosis, diabetes mellitus, primary biliary cirrhosis, etc.) autoimmune diseases, in which low level of vitamin D was found comparing to healthy subjects. In addition, we discuss the correlations between vitamin D levels and clinical manifestations and/or activity of diseases. In this context, we address the rational for vitamin D supplementation in patients suffering from autoimmune diseases. Further studies addressing the mechanisms by which vitamin D affects autoimmunity and the proper supplementation required are needed.     

The Emerging Role of Leptin Antagonist as Potential Therapeutic Option for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disorder that affects millions of people around the world. Leptin is a satiety hormone produced primarily by adipose tissue and acts both centrally and peripherally. Leptin has been shown to play a major role in regulating metabolism, which increases during IBD progression. Leptin mediates several physiological functions including elevated blood pressure, tumorogenesis, cardiovascular pathologies and enhanced immune response in many autoimmune diseases. Recent development of a leptin mutant antagonist that blocks leptin activity raises great hope and opens up new possibilities for therapy in many autoimmune diseases including IBD. To this end, preliminary data from an ongoing study in our laboratory on pegylated leptin antagonist mutant L39A/D40A/F41A (PEG-MLA) treatment shows an inhibition of chronic colitis in IL-10^?/? mice. PEG-MLA effectively attenuates the overall clinical scores, reverses colitis-associated pathogenesis including a decrease in body weight, and decreases systemic leptin level. PEG-MLA induces both central and peripheral leptin deficiency by mediating the cellular immune response. In summary, after blocking leptin activity, the correlative outcome between leptin-mediated cellular immune response, systemic leptin levels, and amount of adipose tissue together may provide new strategies for therapeutic intervention in autoimmune diseases, especially for intestinal inflammation.     

Lymphocyte activation gene-3 (LAG-3) regulatory T cells: An evolving biomarker for treatment response in autoimmune diseases

Regulatory T cells (Tregs) comprise a CD4⁺CD25⁺Foxp3⁺ T cell subset for maintaining immune tolerance, and their deficits and/or dysfunction are observed in autoimmune diseases. The lymphocyte activation gene 3 (LAG-3, also known as CD223), which is an immunoglobulin superfamily member expressed on peripheral immune cells, is recognized as an inhibitory regulator of Tregs. LAG-3⁺ T cells represent a novel protective Tregs subset that produces interleukin-10. Alterations in LAG-3⁺ Tregs have been reported in several autoimmune diseases, suggesting their potential pathogenic role. Recent studies have indicated that LAG-3⁺ Tregs may be associated not only with immunopathology but also with response to therapy in several autoimmune and autoinflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis and others. We present a review of Tregs phenotypes and functions, with a focus on LAG-3⁺ Tregs, and discuss their potential role as biomarkers for treatment response in autoimmune diseases.     

Metabolic pathways in T cell fate and function

T cell growth and function must be tightly regulated to provide protection against foreign pathogens, while avoiding autoimmunity and immunodeficiency. It is now apparent that T cell metabolism is highly dynamic and has a tremendous impact on the ability of T cells to grow, activate and differentiate. Specific metabolic pathways provide energy and biosynthetic precursors that must support specific cell functions, as effector, regulatory, memory, and alloreactive T cells have distinct metabolic needs in immunity and inflammation. Here, we review the signaling pathways that control metabolism and how the metabolic phenotypes of T cell subtypes integrate with T cell function. Ultimately, these metabolic differences may provide new opportunities to modulate the immune response and treat inflammatory and autoimmune diseases.     

Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms

Immunometabolism has emerged as a major mechanism central to adaptive and innate immune regulation. From early observations that inflammatory cytokines were induced in obese adipose tissue and that these cytokines contributed to metabolic disease, it was clear that metabolism and the immunological state are inextricably linked. With a second research wave arising from studies in cancer metabolism to also study the intrinsic metabolic pathways of immune cells themselves and how those pathways influence cell fate and function, immunometabolism is a rapidly maturing area of research. Several key themes and goals drive the field. There is abundant evidence that metabolic pathways are closely tied to cell signaling and differentiation which leads different subsets of immune cells to adopt unique metabolic programs specific to their state and environment. In this way, metabolic signaling drives cell fate. It is also apparent that microenvironment greatly influences cell metabolism. Immune cells adopt programs specific for the tissues where they infiltrate and reside. Ultimately, a central goal of the field is to apply immunometabolism findings to the discovery of novel therapeutic strategies in a wide range of diseases, including cancer, autoimmunity, and metabolic syndrome. This review summarizes these facets of immunometabolism and highlights opportunities for clinical translation.     

Sexual dimorphism in immunometabolism and autoimmunity: Impact on personalized medicine

Immune cells play essential roles in metabolic homeostasis and thus, undergo analogous changes in normal physiology (e.g., puberty and pregnancy) and in various metabolic and immune diseases. An essential component of this close relationship between the two is sex differences. Many autoimmune diseases, such as systemic lupus erythematous and multiple sclerosis, feature strikingly increased prevalence in females, whereas in contrast, infectious diseases, such as Ebola and Middle East Respiratory Syndrome, affect more men than women. Therefore, there are fundamental aspects of metabolic homeostasis and immune functions that are regulated differently in males and females. This can be observed in sex hormone-immune interaction where androgens, such as testosterone, have shown immunosuppressive effects whilst estrogen is on the opposite side of the spectrum with immunoenhancing facilitation of mechanisms. In addition, the two sexes exhibit significant differences in metabolic regulation, with estrous cycles in females known to induce variability in traits and more pronounced metabolic disease phenotype exhibited by males. It is likely that these differences underlie both the development of metabolic and autoimmune diseases and the response to current treatment options. Sexual dimorphism in immunometabolism has emerged to become an area of intense research, aiming to uncover sex-biased effector molecules in the various metabolic tissues and immune cell types, identify sex-biased cell-type-specific functions of common effector molecules, and understand whether the sex differences in metabolic and immune functions influence each other during autoimmune pathogenesis. In this review, we will summarize recent findings that address these critical questions of sexual dimorphism in immunometabolism as well as their translational implications for the clinical management of autoimmune diseases.     

Multiple sclerosis,the microbiome,TLR2, and the hygiene hypothesis

The pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) involves a complex interaction between genetic and environmental factors. Studies of monozygotic twins suggest a significant role for environmental factors in susceptibility to MS. Numerous studies, driven by the “Hygiene Hypothesis,” have focused on the role of environmental factors in allergic and autoimmune diseases. The hygiene hypothesis postulates that individuals living in environments that are too “clean” lack the requisite exposure to “immune-tolerizing” microbial products, resulting in poorly regulated immune systems and increased immune-mediated diseases. Interestingly, few studies have linked MS with the hygiene hypothesis. Similarly, although numerous studies have examined the role of the microbiome in autoimmune diseases, there has been no consistent documentation of disease-specific alterations in the MS microbiome. In this review, we present evidence that integrating the hygiene hypothesis and the microbiome allows for the identification of novel pathophysiologic mechanisms in MS.Our central hypothesis is that the microbiome in MS represents a “defective environment” that fails to provide normal levels of “TLR2-tolerizing” bacterial products to the systemic immune system. Consistent with the hygiene hypothesis, we posit that this defective microbiome function results in abnormally regulated systemic innate immune TLR2 responses that play a critical role in both the inflammatory and defective remyelinative aspects of MS. We have completed proof of concept studies that support the inflammatory, remyelinating, and human immune response components of this paradigm. Our studies suggest that induction of TLR2 tolerance may represent a novel approach to treating MS, inhibiting autoimmune inflammation while simultaneously facilitating remyelination.     

Th9 cells and IL-9 in autoimmune disorders: Pathogenesis and therapeutic potentials

Naïve CD4⁺ T cells are pleiotropically divided into various T helper (Th) cell subsets, according to their pivotal roles in the regulation of immune responses. The differentiation of Th9 cells, an interleukin (IL)-9 producing subset, can be impacted by specific environmental cues, co-stimulation with transforming growth factor β (TGF-β) and IL-4, and other regulatory factors. Although IL-9 has been recognized as a classical Th2-related cytokine, recent studies have indicated that IL-9-producing cells contribute to a group of autoimmune disorders including systemic lupus erythematosus (SLE), multiple sclerosis (MS), inflammatory bowel diseases (IBD), rheumatoid arthritis (RA) and psoriasis. Studies of Th9 cells in autoimmune diseases, although in their infancy, are expected to be of growing interest in the study of potential mechanisms of cytokine regulatory pathways and autoimmune pathogenesis. Several in vitro and in vivo pre-clinical trials have been conducted to explore potential therapeutic strategies by targeting the IL-9 pathway. Specifically, anti-IL-9 monoclonal antibodies (mAbs) and IL-9 inhibitors may potentially be used for the clinical treatment of allergic diseases, autoimmune diseases or cancers. Here, we review recent research on Th9 cells and IL-9 pertaining to cell differentiation, biological characteristics and pivotal cellular inter-relationships implicated in the development of various diseases.     

Impact of intracellular innate immune receptors on immunometabolism

Immunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K–AKT–mTOR and LKB1–AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.     

The microbiome in autoimmune diseases

The microbiome is represented by microorganisms which live in a symbiotic way with the mammalian. Microorganisms have the ability to influence different physiological aspects such as the immune system, metabolism and behaviour. In recent years, several studies have highlighted the role of the microbiome in the pathogenesis of autoimmune diseases. Notably, in systemic lupus erythematosus an alteration of the intestinal flora (lower Firmicutes/Bacteroidetes ratio) has been described. Conversely, changes to the gut commensal and periodontal disease have been proposed as important factors in the pathogenesis of rheumatoid arthritis. At the same time, other autoimmune diseases (i.e. systemic sclerosis, Sjögren’s syndrome and anti-phospholipid syndrome) also share modifications of the microbiome in the intestinal tract and oral flora. Herein, we describe the role of the microbiome in the maintenance homeostasis of the immune system and then the alterations of the microorganisms that occur in systemic autoimmune diseases. Finally, we will consider the use of probiotics and faecal transplantation as novel therapeutic targets.     

The clinical and mechanistic intersection of primary atopic disorders and inborn errors of growth and metabolism

Dynamic changes in metabolism have long been understood as critical for both the initiation and maintenance of innate and adaptive immune responses. A number of recent advances have clarified details of how metabolic pathways can specifically affect cellular function in immune cells. Critical to this understanding is ongoing study of the congenital disorders of glycosylation and other genetic disorders of metabolism that lead to altered immune function in humans. While there are a number of immune phenotypes associated with metabolic derangements caused by single gene disorders, several genetic mutations have begun to link discrete alterations in metabolism and growth specifically with allergic disease. This subset of primary atopic disorders is of particular interest as they illuminate how hypomorphic mutations which allow for some residual function of mutated protein products permit the “abnormal” allergic response. This review will highlight how mutations altering sugar metabolism and mTOR activation place similar constraints on T lymphocyte metabolism to engender atopy, and how alterations in JAK/STAT signaling can impair growth and cellular metabolism while concomitantly promoting allergic diseases and reactions in humans.     

Divergent mechanisms of metabolic dysfunction drive fibroblast and T-cell senescence

The impact of cellular senescence during ageing is well established, however senescence is now recognised to play a role in a variety of age related and metabolic diseases, such as cancer, autoimmune and cardiovascular diseases. It is therefore crucial to gain a better understanding of the mechanisms that control cellular senescence. In recent years our understanding of the intimate relationship between cell metabolism, cell signalling and cellular senescence has greatly improved. In this review we discuss the differing roles of glucose and protein metabolism in both senescent fibroblast and CD8⁺ T-cells, and explore the impact cellular metabolism has on the senescence-associated secretory phenotype (SASP) of these cell types.     

Impacts of the apoptosis inhibitor of macrophage (AIM) on obesity-associated inflammatory diseases

Obesity is associated with various metabolic and cardiovascular diseases caused by chronic, low-grade inflammation that is initially observed in obese adipose tissue. In addition, many etiological studies in humans have shown a strong correlation between obesity and inflammatory autoimmune diseases. In this review, we focus on the involvement of apoptosis inhibitor of macrophage (AIM), a macrophage-derived blood protein, in both types of immune response. Through differential mechanisms, AIM thereby plays key roles in the pathogenesis of atherosclerosis, metabolic diseases, and obesity-associated autoimmune diseases. Thus, the regulation of blood AIM levels or AIM function has the potential to serve as a next-generation therapy against these inflammatory diseases brought about by modern lifestyle.     

The paradigm of Th1 and Th2 cytokines

In the past few years, considerable evidence has accumulated to suggest the existence of functionally polarized responses by the CD4⁺ T helper (Th)—and the CD8⁺ T cytotoxic (Tc)—cell subsets that depend on the cytokines they produce. The Th1 and Th2 cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The factors responsible for the polarization of specific immune response into a predominant Th1 or Th2 profile have been extensively investigated in mice and humans. Evidence has accumulated from animal models to suggest that Th1type lymphokines are involved in the genesis of organ-specific autoimmune diseases, such as experimental autoimmune uveitis, experimental allergic encephalomyelitis, or insulin-dependent diabetes mellitus. Accordingly, data so far available in human diseases favor a prevalent Th1 lymphokine profile in target organs of patients with organ-specific autoimmunity. By contrast, Th2-cell predominance was found in the skin of patients with chronic graft-versus host disease, progressive systemic sclerosis, systemic lupus erythematosus, and allergic diseases. The Th1/Th2 concept suggests that modulation of relative contribution of Th1 or Th2-type cytokines regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologie disorders. In this review, we have discussed the paradigm of Th1 and Th2 cytokines in relation to autoimmunity and allergy.     

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

Recent studies support the notion that glycolysis and oxidative phosphorylation are rheostats in immune cells whose bioenergetics have functional outputs in terms of their biology. Specific intrinsic and extrinsic molecular factors function as molecular potentiometers to adjust and control glycolytic to respiratory power output. In many cases, these potentiometers are used by influenza viruses and immune cells to support pathogenesis and the host immune response, respectively. Influenza virus infects the respiratory tract, providing a specific environmental niche, while immune cells encounter variable nutrient concentrations as they migrate in response to infection. Immune cell subsets have distinct metabolic programs that adjust to meet energetic and biosynthetic requirements to support effector functions, differentiation, and longevity in their ever-changing microenvironments. This review details how influenza coopts the host cell for metabolic reprogramming and describes the overlap of these regulatory controls in immune cells whose function and fate are dictated by metabolism. These details are contextualized with emerging evidence of the consequences of influenza-induced changes in metabolic homeostasis on disease progression.     

Systems-based approaches to study immunometabolism

Technical advances at the interface of biology and computation, such as single-cell RNA-sequencing (scRNA-seq), reveal new layers of complexity in cellular systems. An emerging area of investigation using the systems biology approach is the study of the metabolism of immune cells. The diverse spectra of immune cell phenotypes, sparsity of immune cell numbers in vivo, limitations in the number of metabolites identified, dynamic nature of cellular metabolism and metabolic fluxes, tissue specificity, and high dependence on the local milieu make investigations in immunometabolism challenging, especially at the single-cell level. In this review, we define the systemic nature of immunometabolism, summarize cell- and system-based approaches, and introduce mathematical modeling approaches for systems interrogation of metabolic changes in immune cells. We close the review by discussing the applications and shortcomings of metabolic modeling techniques. With systems-oriented studies of metabolism expected to become a mainstay of immunological research, an understanding of current approaches toward systems immunometabolism will help investigators make the best use of current resources and push the boundaries of the discipline.     

Subsets, expansion and activation of myeloid-derived suppressor cells

Tumor cells and microorganisms manipulate the immune system to minimize any counter response in order to survive. Myeloid-derived suppressor cells (MDSC) in the mouse represent activated Gr-1⁺ CD11b⁺ myeloid precursor cells. Activation may occur through endogenous or exogenous factors leading to the suppression of immune responses. Under steady state conditions the same precursors differentiate into dendritic cells, macrophages and neutrophils. Their linkage to tumor progression and several suppression mechanisms employing the arginine metabolism are well documented, but knowledge of their role in chronic infections, autoimmune diseases and graft-versus-host reactions is just emerging. Several factors have been described to promote MDSC expansion and activation in bone marrow, spleen and tumor sites. New evidence suggests that the Gr-1 antibody itself may differentially trigger myelopoiesis under steady state conditions or induce apoptosis in inflammatory situations after binding to a common epitope expressed on Ly-6C and Ly-6G molecules, respectively. Moreover, two subsets of neutrophil- and monocyte-related MDSC have been described in tumor-bearing and healthy mice. In the present review, we summarize some early work leading to recent findings on these two MDSC subsets, the factors supporting MDSC expansion and activation, as well as novel insights on Gr-1 antibody functions.