Interferon‐α promotes MHC I antigen presentation of islet β cells through STAT1‐IRF7 pathway in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a T cell‐mediated autoimmune disease. Increased incidence of T1D was reported in patients receiving IFN‐α treatment. However, the exact mechanisms of IFN‐α that facilitate the pathogenesis of T1D are not fully understood. To explore the mechanism of IFN‐α on the immune system and islets, non‐obese diabetic (NOD) mice were injected with IFN‐α and the progression of autoimmune insulitis was assessed by haematoxylin and eosin (HE) staining, immunohistochemical and flow cytometry analysis. Transcriptional profiling of islets treated with IFN‐α was explored by RNA‐seq. IFN‐α induced antigen presentation was evaluated by qRT‐PCR, western blot and immunofluorescence, and key transcription factors were inhibited by small interfering RNAs (siRNAs). Our data show that IFN‐α contributed to the progression of autoimmune insulitis in NOD mice by promoting the proliferation of CD8+ T cells. IFN‐α upregulated antigen presentation related genes MHC I, TAP1, B2M, PSMB8, NLRC5 and transcriptional regulator STAT1, STAT2, IRF7 at a time and dose‐dependent manner. The silence of STAT1 or STAT2 both weakened IFN‐α‐induced increase of antigen presenting related molecules. IRF7 was also merely influenced by STAT1 silence. The knockdown of IRF7 decreased the IFN‐α induced expressions of TAP1, PSMB8 and MHC I and prevented the expression of STAT2 but not STAT1. Our study demonstrated that STAT1‐IRF7‐MHC I complex axis were crucial for IFN‐α signalling in islets, and created positive feedback through IRF7‐STAT2 cascade amplifying signals which accelerated the process of T1D.

STING agonist diABZI enhances the cytotoxicity of T cell towards cancer cells

“…It reported that phosphorylation of STAT1 increase the MHC1 antigen presentation [ 30 ]. We investigated the phosphorylation of STAT1 in cells and tumors after stimulation or treatment with STING agonist diABZI.…”

Phosphorylation of aryl hydrocarbon receptor interacting protein by TBK1 negatively regulates IRF7 and the type I interferon response

“…AIP phosphorylation may be coupled to its destabilization as a mechanism to restore the inducibility of IRF7 activation and the inflammatory response. Immune homeostasis requires sufficient negative regulation to prevent autoimmune disease ( 17 , 18 , 19 , 20 , 21 , 22 , 23 , 40 , 41 ) balanced with immune activation to prevent severe and systemic infection ( 13 , 14 ).

Figure 6 Model depicting the proposed role of AIP in the suppression of IRF7 and innate antiviral signaling.

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“…, influenza A virus and COVID-19) ( 15 , 16 ) and autoimmune diseases. Overactivation of IRF7 has been implicated in systemic lupus erythematosus, scleroderma, and type I diabetes ( 17 , 18 , 19 ). Although the mechanisms of negative regulation of RLR signaling have been well described ( 1 , 20 , 21 , 22 , 23 ), how IRF7 is negatively regulated remains poorly understood.…”

Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice

“…Immunofluorescence was performed on the paraffin-embedded pancreas sections. Pancreases were fixed, processed, stained and quantified as previously reported [ 22 ]. See ESM Methods for further details.…”