SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1–Nrf2

Abstract

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate (ECAR) as a measure of glycolysis and the oxygen consumption rate (OCR) as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency (PAD). The highest OCR values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine IL-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in PAD. 3 Primary immunodeficiency disorders (PIDs) are rare genetic syndromes arising from defects in the immune system 1. The majority of PID patients display primary antibody deficiency (PAD) that can develop due to B cell intrinsic defects 2. The causes and genetic background of PADs are complex and pathogenic mutations have been identified only in a minority of cases 3, 4, 5. PADs present with a spectrum of clinical problems, ranging from infections to autoinflammation, autoimmunity, lymphoproliferation and enteropathy. Non-infectious complications are typically unaffected by immunoglobulin replacement therapy and contribute to excess mortality 6. The spectrum of clinical presentation is broad even in patients harboring the same pathogenic mutations, pointing to disease modifiers shaping clinical features 6. Cellular metabolism governs immune cell function 7, 8, 9. Specifically, various facets of glycolysis and glutaminolysis impact the function of B cells 10, 11, 12, 13. Glutaminolysis can contribute to ATP production, and glutamine-derived α-ketoglutarate (α-KG) serves as an anaplerotic source of tricarboxylic acid (TCA) cycle metabolites 14. Mitochondrial oxidative phosphorylation (OxPhos) produces most of the ATP required for anabolic processes in immune cells 15. Non-bioenergetic features of mitochondria also regulate immune cell function. Production of mitochondrial reactive oxygen species (mROS) has been linked to the activation of the transcription factor NFAT in CD4 + T cells and to inhibition of the B cell antigen receptor (BCR) signaling in B cells 16, 17. In T cells, mitochondrial function and epigenetic remodeling are interlinked via pyruvate oxidation and conversion of pyruvate-derived citrate to acetyl-CoA, which is required for histone acetylation 18, 19. Metabolites of the TCA cycle can also directly activate (a-KG), or inhibit (fumarate, succinate) dioxygenases involved in histone and DNA demethylation, thus modulating transcriptional activity. This process of m...

Characterization of the Inducible and Slow-Releasing Hydrogen Sulfide and Persulfide Donor P*: Insights into Hydrogen Sulfide Signaling

“…However, silencing Nrf2 expression also diminished IL-6 levels significantl, y and P* further enhanced the observed decline. Similar to our results, Nrf2 activation was described to directly induce IL-6 transcription in hepatocytes [78] and persistent polyclonal B cell lymphocytosis B cells [79], indicating that Nrf2 suppresses pro-inflammatory markers dependent on the cell type and context. In addition, the antioxidant NAC significantly abolished P*-mediated HO-1 induction, but it did not affect the P*-mediated IL-6 decrease.…”

NRF2, a Transcription Factor for Stress Response and Beyond

“…However, inhibition of pro-inflammatory cytokines by NRF2 is cell type-and context-dependent. In hepatocytes [130] and in persistent polyclonal B cell lymphocytosis B cells [131], NRF2 activation directly induces the transcription of IL-6. Furthermore, NRF2 directly upregulates the expression of MARCO gene, encoding a scavenger receptor required for bacterial phagocytosis, thereby improving bacterial clearance [132].…”

Immunometabolism: From basic mechanisms to translation

“…With clear examples, such as glycogen storage disease-1b that leads to lymphopenia and diminished ability of T cells to upregulate glycolysis, it is apparent that these human genetic diseases can provide a wide-ranging opportunity for immunometabolic discovery. Indeed, screening patients with immune disorders for metabolic phenotypes recently identified gain-of-function mutations in SDH, 60 whereas polymorphisms in ETC proteins were found to lead to increased incidences of infection. 61 In sum, taking this genetic approach based on human disease coupled with biochemical analyses of T cells may reveal new immunometabolic regulators and pathways.…”