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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Nazaroff, CD; Kienzl, M; Schutte, CA; LeSuer, WE; Ochkur, SI; Folmes, CDL; Doyle, AD; Wright, BL; Rank, MA; Krupnick, A; Jacobsen, EA.
IRF1 is an Upstream Regulatory Transcription Factor of Eosinophils in Type 1 Environments.
J Allergy Clin Immunol. 2025; Doi: 10.1016/j.jaci.2025.11.011
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Co-Autor*innen der Med Uni Graz

Kienzl Melanie

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Abstract:

BACKGROUND: Eosinophils have specific immune phenotypes in type 2 and type 1 environments. The regulatory transcription factors (TFs) that control eosinophil activation into type 2 or type 1 immune phenotypes 'E2' or' E1', respectively, are unknown. OBJECTIVE: The goal was to compare mouse and human eosinophil immune phenotypes following exposure to type 2 or type 1 polarizing cytokines and identify TFs that may regulate these responses. METHODS: Peripheral blood eosinophils were isolated from wild type mice and from healthy human donors. Cells were cultured with type 2 (IL-4, GM-CSF, IL-33) or type 1 (IFNγ /TNFα) cytokines. Cells underwent characterization of morphology, gene or protein expression, and bulk RNA sequencing. Bone marrow-derived wild type and interferon regulatory factor (IRF)-deficient mouse eosinophils were generated and analyzed. RESULTS: Mouse and human eosinophils both demonstrated type 2 or type 1 cytokine/chemokine production per E2 or E1 condition. Gene set enrichment revealed similar pathways were upregulated in mouse and human E2 or E1 eosinophils, respectively. Upstream TF regulatory networks were identified as similar between species per E2 or E1 condition. In particular, IRF1 expression increased significantly in E1 conditions for mouse and human eosinophils. IRF1-deficient mouse eosinophils had significant increases in type 2 cytokine and chemokine production concurrent with reduced Nos2, Stat1, IL-12b, and PDL1 when in E1 conditions. CONCLUSIONS: Mouse and human eosinophils have significant similarities in their transcriptomes for their responses to type 2 and type 1 cytokines. IRF1 is increased in mouse and human eosinophils in type 1 environments, and regulates immune responses of mouse eosinophils stimulated with type 1 cytokines.

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