Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.
Bibliographical noteFunding Information:
We thank the patients and their families for participating in the research and all clinical care staff for their contributions. We also thank P. Schwartzberg, P.-P. Axisa and J.-M. Carpier for critical feedback. We thank Prometheus for providing recombinant IL-2 used in T cell culture experiments and the Yale Cancer Center for support. We thank Yale New Haven Hospital and S. Bluell and J. Buell for their support of the Pediatric Genomics Discovery Program. C.L.L. is funded by the Mathers Foundation, National Institute of Allergy and Infectious Diseases/National Institutes of Health (grant no. R01AI150913), Immune Deficiency Foundation, Hood Foundation and Yale University. A.M.M. is funded by a Canada Research Chair (Tier 1) in Pediatric IBD, Canadian Institute of Health Research Foundation Grant, National Institute of Diabetes and Digestive and Kidney Diseases (grant no. RC2DK118640) and the Leona M. and Harry B. Helmsley Charitable Trust.
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.