Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation

Nat Immunol. 2021 Sep;22(9):1118-1126. doi: 10.1038/s41590-021-00984-4.

Paul M Tyler ^# ¹, Molly L Bucklin ^# ¹, Mengting Zhao ^# ¹, Timothy J Maher ¹, Andrew J Rice ¹, Weizhen Ji ² ³, Neil Warner ⁴, Jie Pan ⁴, Raffaella Morotti ⁵, Paul McCarthy ³, Anne Griffiths ⁴, Annemarie M C van Rossum ⁶, Iris H I M Hollink ⁷, Virgil A S H Dalm ⁸, Jason Catanzaro ³, Saquib A Lakhani ² ³, Aleixo M Muise ⁴, Carrie L Lucas ⁹ ¹⁰

Affiliations

1 Immunobiology Department, Yale University School of Medicine, New Haven, CT, USA.
2 Pediatric Genomics Discovery Program, Yale University School of Medicine, New Haven, CT, USA.
3 Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
4 SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.
5 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
6 Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
7 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
8 Department of Internal Medicine, Division of Clinical Immunology and Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
9 Immunobiology Department, Yale University School of Medicine, New Haven, CT, USA. [email protected].
10 Pediatric Genomics Discovery Program, Yale University School of Medicine, New Haven, CT, USA. [email protected].
# Contributed equally.

PMID: 34326534 DOI: 10.1038/s41590-021-00984-4

Abstract

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.

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