Available online 13 August 2022, 104590

1. Interferon regulatory factors (IRFs) are effector transcription factors where distinct nucleic acid sensing pathways converge.

2. IRFs play versatile roles in T1D pathogenesis by affecting the crosstalk between β cells and immune cells, and the reactivity of host to viral infections.

3. Appropriate activation of IRFs is critical to achieve the balance between anti-viral response and the side effect of interferonopathy induced β cell destruction in T1D setting.

Type 1 diabetes (T1D) is an autoimmune disease resulted from the unrestrained inflammatory attack towards the insulin-producing islet β cells. Although the exact etiology underlying T1D remains elusive, viral infections, especially those specific strains of enterovirus, are acknowledged as a critical environmental cue involved in the early phase of disease initiation. Viral infections could either directly impede β cell function, or elicit pathological autoinflammatory reactions for β cell killing. Autoimmune responses are bolstered by a massive body of virus-derived exogenous pathogen-associated molecular patterns (PAMPs) and the presence of β cell-derived damage-associated molecular patterns (DAMPs). In particular, the nucleic acid components and the downstream nucleic acid sensing pathways serve as the major effector mechanism. The endogenous retroviral RNA, mitochondrial DNA (mtDNA) and genomic fragments generated by stressed or dying β cells induce host responses reminiscent of viral infection, a phenomenon termed as viral mimicry during the early stage of T1D development. Given that the interferon regulatory factors (IRFs) are considered as hub transcription factors to modulate immune responses relevant to viral infection, we thus sought to summarize the critical role of IRFs in T1D pathogenesis. We discuss with focus for the impact of IRFs on the sensitivity of β cells to cytokine stimulation, the vulnerability of β cells to viral infection/mimicry, and the intensity of immune response. Together, targeting certain IRF members, alone or together with other therapeutics, could be a promising strategy against T1D.

Interferon Regulatory Factors (IRFs)

Islet β Cells

Immune Response

Type 1 Diabetes (T1D)

© 2022 Published by Elsevier Inc.