ReviewImmunometabolic alterations in lupus: where do they come from and where do we go from there?
Introduction
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease driven by pathogenic autoantibodies that results from the activation of multiple immune-cell types. The overactivation of the lupus immune system has been associated with metabolic alterations in SLE patients as well as in mouse models of the disease, which have been recently reviewed 1, 2 Targeting the altered immunometabolism has been proposed to treat SLE patients 3, 4, which has been validated by clinical trials that have shown that sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, reduced disease activity [5], and metformin, a mild inhibitor of complex 1 in the electron-transport chain, reduced flares [6]. Not surprisingly, the field has grown in complexity from the initial findings of increased mTOR activation and glycolysis in CD4+ T cells [1]. Here, we review the recent literature to discuss the possible origins of the alterations in the metabolism of immune cells in lupus (Figure 1), the dominant role of mitochondrial defects (Figure 2), technological advances that may move the field forward (Figure 3), as well as how targeting lupus immunometabolism may have therapeutic potential (Figure 4).
Section snippets
Genetic factors directly altering immune-cell metabolism
Lupus and many of its endophenotypes have a strong genetic basis with over 80 validated human-susceptibility loci [7]. Among them are polymorphisms in the endogenous retrovirus HRES-1 locus. T cells of SLE patients overexpress HRES-1/Rab4, depleting Drp1 levels, which impairs mitophagy, resulting in the accumulation of defective mitochondria [8]. Treatment with a Rab4 inhibitor restored Drp1 expression and decreased autoimmune pathology in lupus-prone mice, validating this pathway in lupus
Mitochondria dominance in lupus metabolism
Multiple studies using a broad variety of approaches have identified defective mitochondria as a hub of metabolic defects in lupus, which has been the topic of recent reviews 58, 59. Here, we review recent studies that have uncovered novel complex, cell-specific cellular and molecular pathways by which mitochondria contribute to lupus pathogenesis (Figure 2).
Future directions
A requirement for large cell numbers has hampered the metabolomic analysis of immune cells, which present an array of developmental and functional subsets, each of which with probably specific metabolic requirements. Approaches developed to conduct single-cell metabolism 81, 82 have started to be applied to immune cells, such as in vitro-polarized human macrophages [83], and they may be used in autoimmunity research in the near future. Technological advances have also produced promising results
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by the National Institutes of Health RO1AI128901, RO1AI045050, and RO1AI143313.
References and recommended reading (88)
- et al.
Metabolic regulation of pathogenic autoimmunity: therapeutic targeting
Curr Opin Immunol
(2019) - et al.
Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial
Lancet
(2018) - et al.
Safety and efficacy of metformin in systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial
Lancet Rheumatol
(2020) - et al.
There and back again: the journey of the estrogen-related receptors in the cancer realm
J Steroid Biochem Mol Biol
(2016) - et al.
The lupus susceptibility gene Pbx1 regulates the balance between follicular helper T cell and regulatory T cell differentiation
J Immunol
(2016) - et al.
HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells
J Exp Med
(2011) - et al.
Coupled analysis of transcriptome and BCR mutations reveals role of OXPHOS in affinity maturation
Nat Immunol
(2021) - et al.
Intestinal dysbiosis and tryptophan metabolism in autoimmunity
Front Immunol
(2020) - et al.
Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE
Cell
(2021) Oxidative stress in the pathology and treatment of systemic lupus erythematosus
Nat Rev Rheumatol
(2013)
Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice
Lupus Sci Med
Isolevuglandins disrupt PU.1-mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus
JCI Insight
The CD38/NAD/SIRTUIN1/EZH2 axis mitigates cytotoxic CD8 T cell function and identifies patients with SLE prone to infections
Cell Rep
Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes
J Clin Investig
The intersection of cellular and systemic metabolism: Metabolic syndrome in systemic lupus erythematosus
Endocrinol
T cell Metabolism in Lupus
Immunometabolism
Metabolic determinants of lupus pathogenesis
Immunol Rev
Metabolic targets for treatment of autoimmune diseases
Immunometabolism
Genetic advances in systemic lupus erythematosus: an update
Curr Opin Rheuma
HRES-1/Rab4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE
Ann Rheum Dis
Murine lupus susceptibility locus Sle1c2 mediates CD4+ T cell activation and maps to estrogen-related receptor gamma
J Immunol
Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism
JCI Insight
Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets
J Immunol
The nuclear receptor Esrra protects from kidney disease by coupling metabolism and differentiation
Cell Metab
The emerging role of renal tubular epithelial cells in the immunological pathophysiology of lupus nephritis
Front Immunol
IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation
J Clin Investig
Expression of Pbx1b during mammalian organogenesis
Mech Dev
Pre-B cell leukemia homeobox 1 is associated with lupus susceptibility in mice and humans
J Immunol
Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus
Nat Genet
PBX homeobox 1 enhances hair follicle mesenchymal stem cell proliferation and reprogramming through activation of the AKT/glycogen synthase kinase signaling pathway and suppression of apoptosis
Stem Cell Res Ther
Meis1, Hi1α, and GATA1 are integrated into a hierarchical regulatory network to mediate primitive erythropoiesis
FASEB J
Genetic variations controlling regulatory T cell development and activity in mouse models of lupus-like autoimmunity
Front Immunol
Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity
J Clin Investig
Cell-programmed nutrient partitioning in the tumour microenvironment
Nature
Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion
Science
Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells
Nat Commun
Metabolic regulation of follicular helper T cell differentiation in a mouse model of lupus
Immunol Lett
Pharmacologically inferred glycolysis and glutaminolysis requirement of B cells in lupus-prone mice
J Immunol
Germinal center B cells selectively oxidize fatty acids for energy while conducting minimal glycolysis
Nat Immunol
Glycolysis inhibition induces functional and metabolic exhaustion of CD4+ T cells in type 1 diabetes
Front Immunol
Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion
Nat Immunol
Characterization of the metabolic phenotype of chronically activated lymphocytes
Lupus
B cell autophagy mediates TLR7-dependent autoimmunity and inflammation
Autophagy
The habitat filters of microbiota-nourishing immunity
Annu Rev Immunol
Cited by (5)
Immmunometabolism of systemic lupus erythematosus
2024, Clinical ImmunologyAnimal models of lupus nephritis: the past, present and a future outlook
2024, Autoimmunity