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Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases [1]

['Luz P. Blanco', 'Systemic Autoimmunity Branch', 'National Institute Of Arthritis', 'Musculoskeletal', 'Skin Diseases', 'National Institutes Of Health', 'Bethesda', 'Maryland', 'United States Of America', 'Mariana J. Kaplan']

Date: 2023-05 

Abstract Systemic autoimmune diseases are characteristically associated with aberrant autoreactive innate and adaptive immune responses that lead to tissue damage and increased morbidity and mortality. Autoimmunity has been linked to alterations in the metabolic functions of immune cells (immunometabolism) and, more specifically, to mitochondrial dysfunction. Much has been written about immunometabolism in autoimmunity in general, so this Essay focuses on recent research into the role of mitochondrial dysfunction in the dysregulation of innate and adaptive immunity that is characteristic of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Enhancing the understanding of mitochondrial dysregulation in autoimmunity will hopefully contribute to accelerating the development of immunomodulatory treatments for these challenging diseases.

Citation: Blanco LP, Kaplan MJ (2023) Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases. PLoS Biol 21(4): e3002084. https://doi.org/10.1371/journal.pbio.3002084 Published: April 25, 2023 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This work was supported by the Intramural Research Program at NIAMS/NIH through grant NIAMS ZIA AR 041199 (to MJK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: APC, antigen-presenting cell; ATP, adenosine triphosphate; DAMP, danger-associated molecular pattern; DC, dendritic cell; IFN, interferon; ILC, innate lymphoid cell; LDG, low-density granulocytes; mDNA, mitochondrial DNA; MHC, major histocompatibility complex; mROS, mitochondrial reactive oxygen species; NAD, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NET, neutrophil extracellular trap; PRDX6, peroxiredoxin 6; RA, rheumatoid arthritis; ROS, reactive oxygen species; SLE, systemic lupus erythematosus; TCA, tricarboxylic acid; TLR, toll-like receptor; VDAC-1, voltage dependent anion channel-1

Introduction The main function of the human immune system is to protect us against microbes, cancer cells, and other threats through its 2 arms: the innate and adaptive immune systems (Box 1). The immune system requires a delicate and active process that balances antimicrobial effector functions with adequate mechanisms to resolve inflammation and prevent self-damage. Indeed, dysregulated immune responses and an imbalance in these mechanisms can lead to tissue damage, inflammation, and autoimmunity. The term “autoimmunity” covers a myriad of conditions in which the immune system synthesizes or fails to clear antibodies and immune cells that are reactive against self-antigens (also known as autoantigens), triggering damage of the targeted tissues and specific diseases. The road to autoimmunity is complex, multifactorial, and comprises many putative steps involving complex crosstalk between various immune and stromal cells; it is influenced by environmental exposures, genetic and epigenetic factors, and poorly understood stochastic events [1,2]. The metabolism of immune cells is crucial for the regulation of immune activation in homeostasis and disease states. Indeed, metabolism regulates cellular aspects such as proliferation, differentiation, cell fate, and effector functions of immune cells because all these processes depend on proper energy supplies. In addition, cellular metabolism not only regulates energy fluxes but also can affect gene expression by epigenetic modifications (Box 1), adding another layer of complexity to the immunopathogenesis and possible therapeutic targets in autoimmune diseases [3]. In this Essay, we discuss recent findings related to changes in the metabolic functions of immune cells (immunometabolism), particularly mitochondrial dysfunction, in innate and adaptive immune cells and their contribution to the generation of autoimmunity, with emphasis on systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) as examples of systemic autoimmune conditions (Box 1). Box 1. Glossary Innate immune system The body’s first line of defense, quick in its responses and generally nonspecific. The main cellular components are myeloid cells, including granulocytes (neutrophils, eosinophils, and basophils), monocytes, macrophages, and dendritic cells (DCs), but other cells such as gamma delta T cells, innate lymphoid cells (ILCs), and mast cells can be considered part of the innate immune system. Innate immune cells are the first in line to directly detect and effectively destroy threats: endowed with a powerful broad range of antimicrobial molecules and functions, including phagocytic capacity, antigen presentation, synthesis of enzymes, vasoactive factors, pore-forming proteins, chemokines, and cytokines. Adaptive immune system Mostly consists of B cells and T cells, which have powerful and specific mechanisms to destroy and remember pathogens for future encounters, making them essential for vaccine effectivity and immunity against pathogens. Epigenetic modifications A series of chemical modifications of nucleic acids and/or histones to modulate gene expression without changing the genetic code. Some of the modifications include methylation, acetylation, and the recently described lactylation. Immunologic tolerance An active process of the immune system that deals with preventing or reverting antigen-specific autoreactive responses. Systemic lupus erythematosus An autoimmune syndrome characterized by multi-organ damage due to inflammation. Systemic lupus erythematosus (SLE) is characterized by the presence of circulating autoantibodies that recognize double-stranded DNA, histones, and a variety of RNA–protein complexes, among other autoantigens. The formation of immune complexes leads to proinflammatory and pro-oxidative environments and tissue damage. Rheumatoid arthritis Rheumatoid arthritis (RA) is a chronic inflammatory disease in which the synovial joints are targeted by autoantibodies and autoreactive immune cells. In severe cases, the inflammation can also affect other tissues including the heart, lungs, eyes, nerves, and skin. Inflammasome A complex intracellular structure formed by diverse components that assemble together in response to inflammation, oxidative stress, and infectious triggers. Antigen presentation Required to avoid self-recognition and the development of autoreactive immune responses, and to generate enduring protective immunological memory. Antigen-presenting cells (APCs) internalize and process microbes and antigens. Upon processing, the ingested antigens are transformed into peptides. Peptides are presented at the APCs’ membrane by major histocompatibility complex (MHC) class II molecules. Specific T cells recognize the presented MHC–peptide complex, becoming activated. Activated T cells proliferate and engage through their T-cell receptor with the respective antigen-specific B cell (which present the correct membrane-associated MHC–peptide complex) promoting their transition into plasma cells, which synthetize specific antibodies.

Autoimmunity and metabolism The mechanisms by which innate immune cells promote autoimmune responses have become significantly clearer over the past few decades. Overactive innate immune cells responding to microbial triggers or other danger signals might cause tissue damage and undergo or promote inflammatory cell death, generating and modifying endogenous danger-associated molecular patterns (DAMPs), autoantigens or neoantigens [4]. This autoantigen modification may be triggered by a variety of mechanisms, including enhanced inflammatory oxidative stress involving the synthesis of reactive oxygen species (ROS) that can modify nucleic acids, lipids, carbohydrates, and proteins. In predisposed hosts, these neoantigens can contribute to fueling the fire and promote downstream inflammatory responses. Dead cells and cellular debris that are not cleared promptly by innate immune cells can expose modified nuclear and mitochondrial-derived DNA, as well as RNA, that can have potent proinflammatory effects on target cells and activate toll-like receptors (TLRs) and other membrane-bound and cytoplasmic sensors of nucleic acids and associated proteins [4] (Box 2). Box 2. Key points in the generation of autoimmunity and mitochondrial dysfunction ➢ Genetic propensity, environmental stimuli, and stochastic events trigger the generation of proinflammatory and pro-oxidative pathways. ➢ In this milieu, inflammatory cell death and improper clearance of dead cells can trigger and perpetuate neoantigen generation and inflammation. ➢ Dysfunctional mitochondrial function is prevalent and perpetuates in inflammatory conditions and under hypoxia. ➢ Mitochondrial dysfunction affects cells’ metabolism, perturbing regulatory networks, fueling proinflammatory responses, and interfering with immune system homeostasis. Regarding the adaptive immune system, autoreactive T cells can escape the process of thymus education in which they are eliminated before accessing the periphery (areas outside the primary lymphoid organs) [5], where they might cross-recognize microbial products or other danger signals. These products can mimic autoantigens, acting as neoantigens that can lead the adaptive immune cells to trigger unintended autoreactive responses [6]. Additionally, failure in the generation and/or function of regulatory T (T reg ) cells and regulatory B (B reg ) cells, key in the development of immunologic tolerance (Box 1), may also be involved in the induction of autoimmune responses [7]. Immune tolerance responses encompass the development and engagement of specific tolerogenic cellular and humoral responses to retain and also expand mechanisms of immune regulation [8]. Akin to inducing an antigen-specific protective immune response, many steps can go awry and disturb the development of tolerance, promoting autoreactive and autoimmune responses. Indeed, several approaches to promote and restore tolerance have been investigated, including desensitization strategies, oral immunotherapy, HLA desensitization, immunoablation followed by hematopoietic stem cell transplant, as well as vaccines designed to induce tolerogenic responses [9–11]. The development of these opposing (inflammatory versus tolerogenic) immune responses and cellular networks requires specific metabolic responses. Effective immune responses entail heightened cellular metabolism, biosynthetic potential, and cellular division. A shared feature of both inflammatory and cancer cells is a metabolic reprograming activity required for actively dividing cells. This metabolic reprograming in cancer cells, known as the “Warburg effect,” in which cells increase the rate of glucose uptake and preferential production of lactate, takes place in cells that are actively dividing and that have increased demand for biosynthetic molecular precursors and enzyme cofactors [12]. Another shared feature between inflammatory and cancer cells is that they function in hypoxic microenvironments in the tissues they infiltrate. Hypoxia development is frequently observed in inflamed tissues in autoimmune diseases [13] and is a stressor for mitochondria that triggers the electron transport chain to work in reverse flow. As such, instead of producing adenosine triphosphate (ATP), it generates mitochondrial ROS (mROS) that can further contribute to oxygen consumption. Furthermore, hypoxia promotes the use of fumarate instead of oxygen as the terminal electron acceptor [14,15]. Under hypoxic and/or inflammatory conditions, mitochondria are not fully functional and display impaired ability to provide nicotinamide adenine dinucleotide (NAD+) coenzyme, leading to activation of alternative cellular metabolic cycles such as glycolysis to provide both ATP and NAD+ [16]. Due to increased glycolytic activity, acidification may ensue through enhanced lactic acid generation. Cellular damage can then be quickly amplified due to further promote mitochondrial dysfunction. It is important to consider that these metabolic pathway adjustments are essential for the survival of cells and to effectively fight infections; therefore, they cannot be completely blunted. As such, it is imperative to learn in more detail how to harmonize the balance among these pathways to avoid aberrant inflammatory responses while mounting an adequate antimicrobial response (Box 2).

Modulation of mitochondrial dysfunction Given the link between mitochondrial dysfunction and type I IFN synthesis, it has been hypothesized that modulating or improving aberrant neutrophil mitochondrial dysfunction and myeloid bioenergetics could have beneficial effects in SLE. Indeed, mROS scavengers and inhibitors of VDAC oligomerization can attenuate lupus features in mice and normalize dysregulated neutrophil responses [18,28]. Administration of analogs of the essential electron carrier coenzyme Q, such as idebenone or MitoQ, to improve mitochondrial function also had beneficial effects on murine lupus models [54,55]. Itaconate, a TCA cycle mitochondrial-derived metabolite produced in response to inflammation, blunts oxidative stress, proinflammatory, and type I IFN-generating responses [56]. Lupus mice treated with an itaconate derivative showed significant attenuation of disease progression [57]. Furthermore, repairing the activity of oxyguanine glycosylase 1 (OGG1), an enzyme involved in excising damaged oxidized nucleic acids, attenuated skin lesions and immune dysregulation in pristane-induced murine lupus [58]. Despite all the caveats related to global modulation of immunometabolism in autoimmunity, there is also promising data in which systemic treatment with metformin (to attenuate mitochondrial function) together with 2-deoxyglucose (to reduce exacerbated glycolysis) displayed beneficial effects in murine lupus models and in vitro experiments with T cells from patients with SLE [59,60]. However, whether these potentially promising preclinical observations following manipulation of mitochondrial dysfunction and immunometabolism will be recapitulated in patients with SLE remains to be determined.

Conclusion Significant advances in understanding mitochondrial physiology and metabolism in immune cells highlight that targeting abnormalities in these pathways could benefit the treatment of autoimmune diseases. Indeed, future research should focus on developing strategies to generate effective immune tolerance, mitigate mitochondrial dysfunction, and enhance mitochondrial functionality. More research into metabolic dysfunction in various immune cell subsets in autoimmunity, its triggers, and cell-specific versus systemic effects will be needed before more targeted approaches can be designed. Efforts toward modifying aberrant mitochondrial physiology may help prevent or revert tissue damage in systemic inflammatory conditions. Given the complex effects of immune metabolism in homeostasis and disease, it remains unclear whether these approaches could also promote significant deleterious effects. It is expected that the next decade, with the significant advances in multi-omic approaches and disease pathophysiology will clarify the benefit, risks, and feasibility of targeting mitochondrial dysfunction in chronic autoimmune diseases.

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002084

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