Review
Immunometabolic alterations in lupus: where do they come from and where do we go from there?

https://doi.org/10.1016/j.coi.2022.102245Get rights and content

Highlights

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    Immunometabolism dysregulations in lupus have multifactorial origins.

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    Contributing factors include genetics and chronic autoantigen stimulation.

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    Metabolites from dysbiotic microbiota may regulate immune-cell metabolism.

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    Autoimmune activation and altered cellular metabolism are deeply interconnected.

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    Novel metabolic targets have been identified as potential therapies in lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the overactivation of the immune system has been associated with metabolic alterations. Targeting the altered immunometabolism has been proposed to treat SLE patients based on their results obtained and mouse models of the disease. Here, we review the recent literature to discuss the possible origins of the alterations in the metabolism of immune cells in lupus, the dominant role of mitochondrial defects, technological advances that may move the field forward, as well as how targeting lupus immunometabolism may have therapeutic potential.

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.

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