Background/Purpose: Hypoxia inducible factor 1 is a key transcription factor that regulates the cellular response to oxygen stress. In the adaptive immune system, HIF-1α is mainly expressed by CD4⁺ T cells in response to TCR ligation and enhanced by exposure to inflammatory cytokines. Transcriptional activation of HIF-responsive genes influence T cell differentiation and function. MicroRNAs are a class of endogenous non‐coding RNAs that exert a regulatory influence on almost every aspect of cellular biology. Aberrant expression of many miRNAs have been shown to correlate with poor clinical outcome across a wide spectrum of diseases. MiR-210 is a hypoxia-responsive miRNA transcriptionally regulated by HIF-1α. HIF-1α is also a direct miR-210 target suggesting an important role for miR-210 in regulation of T cell response. Abnormal T cell function is increasingly recognized as a major contributing factor in SLE immunopathology however, the expression and function of HIF-1α and miR-210 in SLE remains largely unexplored.

Methods: Lymphocyte subsets were purified from lupus-prone Sle123 mice with mild or severe disease and from age-matched WT controls and assayed for miR-210 expression by real-time RT-PCR. Peripheral lymphocytes were purified from human SLE patients and healthy subjects and assayed for HIF-1α, miR-210, RORγt and IL-17 expression by real-time RT-PCR. Mean, error and significance values were determined using an unpaired Student’s t test assuming equal variance. p values < 0.05 were considered significant. All animal procedures were conducted under an approved IACUC protocol. Human peripheral blood samples were collected with prior written informed consent under an approved IRB protocol.

Results: CD4⁺, CD8⁺ and CD19⁺ lymphocyte subsets were purified from Sle123 mice with mild or severe disease and assayed for miR-210 expression by real-time PCR. MiR-210 expression was similar across subsets from mice with mild disease compared to age/sex-matched wild-type controls. MiR-210 was 352-fold up-regulated in the CD4⁺ T cell subset from mice with advanced disease and 2.3-fold and 2.5-fold up-regulated in the CD8⁺ and CD19⁺ lineages respectively. p < 0.001 (CD4⁺ and CD8⁺) and < 0.01 (CD19⁺), n = 3. We purified peripheral blood mononuclear cells (PBMC) from lupus patients with active disease and quantified HIF-1α and miR-210 expression levels by qRT-PCR. We measured 5.3 HIF-1α and 43.4-fold miR-210 differential-expression in human SLE PBMCs compared to healthy controls (p < 0.001 (miR-210) and < 0.05 (HIF-1α), n = 4. RORγt and IL-17 expression associate with HIF-1α and miR-210 activity. We purified peripheral lymphocytes from human lupus patients with active disease and healthy controls and assayed for RORγt and IL-17 expression by qRT-PCR. We measured 4.6-fold RORγt differential-expression and 3.2-fold differential-expression of its transcriptional target IL-17. p < 0.001 (RORγt) and < 0.05 (IL-17), n = 4.

Conclusion: Our results suggest that HIF-1α may play an important and previously unrecognized role in the pathobiology of SLE. HIF-1α and HIF-1a regulated pathways may represent a novel and productive direction for future etiological studies in lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hif-1%ce%b1-and-mir-210-differential-and-lineage-specific-expression-in-systemic-lupus-erythematosus/