Journal Article

Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation

Lucas, Carrie L., Dalm, Virgil A.S.H., Ji, Weizhen, Catanzaro, Jason, Tyler, Paul M., Muise, Aleixo M., McCarthy, Paul, Bucklin, Molly L., Griffiths, Anne, Zhao, Mengting, Lakhani, Saquib A., Maher, Timothy J., Hollink, Iris H.I.M., Morotti, Raffaella, van Rossum, Annemarie M. C., Rice, Andrew J., Warner, Neil, Pan, Jie

2021

Overview

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. Lucas and colleagues describe loss-of-function variants in the X-linked ETS transcription factor ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD)-like features.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/249/2510/2511 / 631/250/249/2512 / Animal models / Animals / Autoimmune diseases / Biomedical and Life Sciences / Biomedicine / Calgranulin A - metabolism / Chemotactic factors / Colorectal diseases / Development and progression / DNA-Binding Proteins - genetics / ETS protein / Female / Gastrointestinal diseases / Gene Expression Regulation - genetics / Genetic aspects / Health aspects / Hereditary Autoinflammatory Diseases - genetics / Hereditary Autoinflammatory Diseases - immunology / Hereditary Autoinflammatory Diseases - pathology / Humans / Immunology / Infectious Diseases / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - genetics / Inflammatory Bowel Diseases - immunology / Inflammatory Bowel Diseases - pathology / Inflammatory diseases / Interleukin 1 / Interleukin 1 Receptor Antagonist Protein - immunology / Interleukin 12 / Intestine / Leukocytes (neutrophilic) / Lipocalin-2 - metabolism / Lipopolysaccharides / Lipopolysaccharides - toxicity / Macrophages / Macrophages - immunology / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Mucosa / Th17 Cells - immunology / Transcription factors / Transcription Factors - genetics / Transcription, Genetic - genetics / Triggering Receptor Expressed on Myeloid Cells-1 - antagonists & inhibitors / Triggering Receptor Expressed on Myeloid Cells-1 - metabolism / Ulcers