IL-13Ra1-mediated signaling regulates ABC expansion and lupus pathogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA848794 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19637433.fastq.gz | Fastqsanger.gz | |||
| SRR19637434.fastq.gz | Fastqsanger.gz | |||
| SRR19637435.fastq.gz | Fastqsanger.gz | |||
| SRR19637436.fastq.gz | Fastqsanger.gz | |||
| SRR19637437.fastq.gz | Fastqsanger.gz |
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2023-02-16 | E-MTAB-12568 | biostudies-arrayexpress
Project description:Aberrant expression of IL-17A together with abated IL-2 production by effector CD4+ T cells contributes to the pathogenesis of systemic lupus erythematosus (SLE). Here we report that Sirtuin 2 (SIRT2), a member of the family of NAD+-dependent histone deacetylases, suppresses IL-2 production by CD4+ T cells while it promotes their differentiation into Th17 cells. Mechanistically, we show that SIRT2 is responsible for the deacetylation of p70S6K and the activation of the mTORC1/HIF-1α/RORγt pathway and the generation of Th17 cells differentiation. Additionally, SIRT2 is responsible for the deacetylation of c-Jun and histones on the Il-2 gene, resulting in decreased IL-2 production. We found that the transcription factor inducible cAMP early repressor (ICER), which is overexpressed in T cells from people with SLE and lupus-prone mice, binds directly to the Sirt2 promoter and promotes its transcription. AK-7, a SIRT2 inhibitor limited the ability of adoptively transferred antigen-specific CD4+ T cells to cause autoimmune encephalomyelitis and disease in the lupus-prone MRL/lpr mice. Finally, CD4+ T cells from SLE patients exhibited increased expression of SIRT2, and pharmacological inhibition of SIRT2 in primary CD4+ T cells from patients with SLE attenuated their ability to differentiate into Th17 cells and promoted IL-2–producing T cells. Collectively, these results suggest that SIRT2-mediated deacetylation is essential for the aberrant expression of IL-17A and IL-2 and that SIRT2 may be a promising molecular target for new therapies for SLE.
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Project description:Our group has proposed that low-density granulocytes (LDGs) play an important role in lupus pathogenesis, as they can damage endothelial cells and synthesize increased levels of proinflammatory cytokines and type I interferons. LDGs have a heightened capacity to synthesize neutrophil extracellular traps (NETs). NETs from LDGs display increased levels of bactericidal and immunostimulatory proteins, such as the cathelicidin LL37 and externalize double-stranded DNA (dsDNA). Lupus netting LDGs have increased capacity to kill endothelial cells and expose IL-17. Through NETosis, lupus neutrophils stimulate plasmacytoid DCs to synthesize IFN-?. Our results further expand the potential pathogenic role of aberrant lupus neutrophils through a NET-mediated effect. We used microarrays to analyze the gene expression of neutrophils in healthy and lupus patients, and of low-density granulocytes in lupus patients. Human neutrophils and LDGs were isolated from PBMCs. RNA from healthy neutrophils, lupus neutrophils and lupus LDGs was extracted and processed for hybridization on Affymetrix microarrays.
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