Exactly how nucleic acids trigger type I interferon responses via certain Toll-like receptors has been uncertain. Now, a new pathway involving gene products previously linked to systemic lupus erythematosus but not known to interact has been unravelled, which could be of relevance to the female sex bias in this disease.
This is a preview of subscription content, log in via an institution to check access.
References
Odhams, C. A. et al. Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in systemic lupus erythematosus. Nat. Commun. 10, 2164 (2019).
Bentham, J. et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat. Genet. 47, 1457–1464 (2015).
Heinz, L. X. et al. TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature 581, 316–322 (2020).
Fitzgerald, K. A. & Kagan, J. C. Toll-like receptors and the control of immunity. Cell 180, 1044–1066 (2020).
Elkon, K. B. Review: cell death, nucleic acids, and immunity: inflammation beyond the grave. Arthritis Rheumatol. 70, 805–816 (2018).
Baccala, R. et al. Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc. Natl Acad. Sci. USA 110, 2940–2945 (2013).
Li, D. et al. IRF5 genetic risk variants drive myeloid-specific IRF5 hyperactivation and presymptomatic SLE. JCI insight 5, e124020 (2020).
Harris, V. M. et al. Lysosomal pH is regulated in a sex dependent manner in immune cells expressing CXorf21. Frontiers Immunol. 10, 578 (2019).
Souyris, M. et al. TLR7 escapes X chromosome inactivation in immune cells. Sci. Immunol. 3, eaap8855 (2018).
Kobayashi, T. et al. The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity 41, 375–388 (2014).
Acknowledgements
The authors thank Jie An and Gillian I. Rice for helpful discussions. The work of the authors is supported by grants from the National Institutes of Health, Lupus Research Alliance and Rheumatology Research Foundation (to K.B.E.) and the Medical Research Foundation and the NIHR Manchester Biomedical Research Centre (to T.B.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Elkon, K.B., Briggs, T.A. The (Orf)ull truth about IRF5 and type I interferons in SLE. Nat Rev Rheumatol 16, 543–544 (2020). https://doi.org/10.1038/s41584-020-0472-7
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41584-020-0472-7
- Springer Nature Limited
This article is cited by
-
Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling
Nature Communications (2023)
-
A Summary on the Genetics of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren’s Syndrome
Clinical Reviews in Allergy & Immunology (2022)