Ifih1, also known as melanoma differentiation-associated protein 5 (MDA5), is an essential innate immune regulator [3,4]. It encodes a cytosolic protein crucial for antiviral host immune responses, mediating the interferon response of the innate immune system to certain viral species that form double-stranded RNA (dsRNA) during their life cycle [3]. The activation of IFIH1-IRF3 can be stimulated by viral RNAs or RNA mimics, and in the case of acute respiratory distress syndrome (ARDS), LPS can also activate IFIH1-IRF3 via a MyD88-dependent mechanism [1].

In ARDS, IFIH1 was identified as a hub gene among 36 candidates associated with ARDS severity and M1 macrophage polarization. Transfection of shIFIH1 lentivirus and IFIH1 plasmid expression vectors in RAW264.7 cell line and BMDMs confirmed that IFIH1 promotes M1 macrophage polarization, and it does so by activating IRF3 [1]. In HIV-1 infection, knockdown of IFIH1 in human monocyte-derived dendritic cells prevented the activation of the interferon-stimulated gene ISG15, indicating that IFIH1 is the innate immune receptor for intron-containing RNA from the HIV-1 provirus [2]. Also, loss-of-function variants of IFIH1 in nine patients were associated with recurrent infections, inflammatory diseases, severe COVID-19 or multisystem inflammatory syndrome in children (MIS-C), along with lymphopaenia and increased inflammatory markers. Expression analysis in a patient with a c.2016delA variant showed disrupted immune response upon stimulation with Poly(I:C) [4].

In conclusion, Ifih1 is a key gene in the innate immune response, playing a crucial role in detecting viral infections and regulating immune-related processes. Its function in promoting M1 macrophage polarization in ARDS, detecting HIV-1 intron-containing RNA, and its association with various inflammatory and infectious diseases, as revealed by in vitro and patient-based studies, highlight its significance in understanding immune-related disease mechanisms.

References:

1. Zhang, Shi, Chu, Cuilin, Wu, Zongsheng, Yang, Yi, Qiu, Haibo. 2021. IFIH1 Contributes to M1 Macrophage Polarization in ARDS. In Frontiers in immunology, 11, 580838. doi:10.3389/fimmu.2020.580838. https://pubmed.ncbi.nlm.nih.gov/33519803/

2. Guney, Mehmet Hakan, Nagalekshmi, Karthika, McCauley, Sean Matthew, Aydemir, Ozkan, Luban, Jeremy. 2024. IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2404349121. doi:10.1073/pnas.2404349121. https://pubmed.ncbi.nlm.nih.gov/38985764/

3. Looney, Benjamin M, Xia, Chang-Qing, Concannon, Patrick, Ostrov, David A, Clare-Salzler, Michael J. . Effects of type 1 diabetes-associated IFIH1 polymorphisms on MDA5 function and expression. In Current diabetes reports, 15, 96. doi:10.1007/s11892-015-0656-8. https://pubmed.ncbi.nlm.nih.gov/26385483/

4. Najm, Rania, Yavuz, Lemis, Jain, Ruchi, Abou Tayoun, Ahmad, Kandasamy, Richard K. 2024. IFIH1 loss of function predisposes to inflammatory and SARS-CoV-2-related infectious diseases. In Scandinavian journal of immunology, 100, e13373. doi:10.1111/sji.13373. https://pubmed.ncbi.nlm.nih.gov/38757311/