Interferon Regulatory Factors as a Potential Therapeutic Target for Neuroinflammation: A Focus on Alzheimer's Disease

Abstract

Interferon Regulatory Factors (IRFs) are critical modulators of immune and inflammatory responses, yet their roles in Alzheimer's disease (AD) and other neurodegenerative disorders remain incompletely understood. While IRFs are recognized for their regulatory functions in neuroinflammation, microglial activation, and neuronal survival, their dual roles as both drivers of pathological inflammation and mediators of neuroprotective pathways underscore a sophisticated regulatory paradox in neurodegenerative disorders. This review aims to synthesize current evidence on IRF-mediated neuroinflammation in AD and related diseases, focusing on the multifaceted functions of key IRF family members, including IRF1, IRF3, and IRF7. We critically evaluate their divergent roles: IRF1 and IRF3, for instance, exacerbate neuroinflammatory cascades and amyloid-beta (Aβ) pathology in AD, whereas IRF7 may paradoxically suppress inflammation under specific conditions. Additionally, we explore IRF dysregulation in Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, emphasizing shared and distinct mechanisms across neurodegenerative disorders. Restoring IRF balance through genetic manipulation, small-molecule inhibitors, or microbiome-derived modulators could attenuate neuroinflammation, enhance Aβ clearance, and protect neuronal integrity. Ultimately, this work provides a framework for future research to harness IRF signaling pathways in the development of precision therapies for AD and other neurodegenerative diseases.

Keywords: Alzheimer’s disease; interferon regulatory factors; neuroinflammation; therapeutic targets.

Figure 1

The regulatory effects and molecular mechanisms of the IRF family in AD-associated neuroinflammation. (a) The role of IRF1 in the phenotypic transformation of microglia. (b) IRF3 modulates neuroinflammation and AD progression via TLR/STING signaling pathways and the interplay between autophagy and pyroptosis. (c) IRF7 modulates AD-associated neuroinflammation via the TLR/STING-miRNA interaction network and microglial M1/M2 phenotypic polarization. (d) The regulatory network of IRF4, IRF5, and IRF8 in microglial polarization.

Figure 2

The potential role of IRFs in other neurodegenerative diseases. (a) IRF1, IRF3, IRF7, IRF8, and IRF9 negatively regulate Parkinson’s disease. (b) IRF1, IRF4, IRF5, and IRF8 present negative roles; IRF7 plays protective roles; and IRF3 plays dual roles in multiple sclerosis. (c) IRF1, IRF3, and IRF5 negatively regulate amyotrophic lateral sclerosis. (d) IRF3 negatively regulates Huntington’s disease.