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Immunohorizons
. 2025 Aug 25;9(9):vlaf032.
doi: 10.1093/immhor/vlaf032. IL-4 and TGF-β regulate inflammatory cytokines and cellular infiltration in the lung and systemic IL-6 in mouse-adapted SARS-CoV-2 infection
Solomon Taye Sima 1 , Lucinda Puebla-Clark 2 3 , Maria Gonzalez-Orozco 4 , Mark Joseph Endrino 1 , Thomas R Shelite 2 , Hsiang-Chi Tseng 5 , Yazmin B Martinez-Martinez 3 , Matthew B Huante 3 , Hannah G Federman 1 , Komi Gbedande 1 2 , Vineet D Menachery 4 , Mark C Siracusa 1 , Mark A Endsley 3 , Sara M Dann 2 , Janice J Endsley 3 , Ricardo Rajsbaum 3 5 , Robin Stephens 1 2 3 6
Affiliations
The pathology of severe COVID-19 is due to a hyperinflammatory immune response persisting after viral clearance. To understand how the immune response to SARS-CoV-2 is regulated to avoid severe COVID-19, we tested relevant immunoregulatory cytokines. Transforming growth factor β (TGF-β), interleukin (IL)-10, and IL-4 were neutralized upon infection with mouse-adapted SARS-CoV-2 (CMA3p20), a model of mild disease; lung inflammation was quantified by histology and flow cytometry at early and late time points. Mild weight loss and lung inflammation including consolidation and alveolar thickening were evident 3 d postinfection (dpi), and inflammation persisted to 7 dpi. Coinciding with early monocytic infiltrates, CCL2 and granulocyte colony-stimulating factor were transiently produced 3 dpi, while IL-12 and CCL5 persisted to 7 dpi, modeling viral and inflammatory phases of disease. Neutralization of TGF-β, but not IL-10 or IL-4, significantly increased lung inflammatory monocytes and elevated serum but not lung IL-6. Neutralization of IL-4 prolonged weight loss and increased early perivascular infiltration without changing viral titer. Anti-IL-4 reduced expression of Arg1, a gene associated with alternative activation of macrophages. Neutralizing TGF-β and IL-4 had differential effects on pathology after virus control. Lung perivascular infiltration was reduced 7 dpi by neutralization of IL-4 or TGF-β, and periairway inflammation was affected by anti-TGF-β, while alveolar infiltrates were not affected by either. Anti-IL-4 prolonged IL-12 to 7 dpi along with reduced IL-10 in lungs. Overall, the immunoregulatory cytokines TGF-β and IL-4 dampen initial inflammation in this mouse-adapted SARS-CoV-2 infection, suggesting that promotion of immunoregulation could help patients in early stages of disease.
Keywords: IL-4; SARS-CoV-2; TGF-β; cytokines; immunoregulation.
. 2025 Aug 25;9(9):vlaf032.
doi: 10.1093/immhor/vlaf032. IL-4 and TGF-β regulate inflammatory cytokines and cellular infiltration in the lung and systemic IL-6 in mouse-adapted SARS-CoV-2 infection
Solomon Taye Sima 1 , Lucinda Puebla-Clark 2 3 , Maria Gonzalez-Orozco 4 , Mark Joseph Endrino 1 , Thomas R Shelite 2 , Hsiang-Chi Tseng 5 , Yazmin B Martinez-Martinez 3 , Matthew B Huante 3 , Hannah G Federman 1 , Komi Gbedande 1 2 , Vineet D Menachery 4 , Mark C Siracusa 1 , Mark A Endsley 3 , Sara M Dann 2 , Janice J Endsley 3 , Ricardo Rajsbaum 3 5 , Robin Stephens 1 2 3 6
Affiliations
- PMID: 40854598
- PMCID: PMC12377903
- DOI: 10.1093/immhor/vlaf032
The pathology of severe COVID-19 is due to a hyperinflammatory immune response persisting after viral clearance. To understand how the immune response to SARS-CoV-2 is regulated to avoid severe COVID-19, we tested relevant immunoregulatory cytokines. Transforming growth factor β (TGF-β), interleukin (IL)-10, and IL-4 were neutralized upon infection with mouse-adapted SARS-CoV-2 (CMA3p20), a model of mild disease; lung inflammation was quantified by histology and flow cytometry at early and late time points. Mild weight loss and lung inflammation including consolidation and alveolar thickening were evident 3 d postinfection (dpi), and inflammation persisted to 7 dpi. Coinciding with early monocytic infiltrates, CCL2 and granulocyte colony-stimulating factor were transiently produced 3 dpi, while IL-12 and CCL5 persisted to 7 dpi, modeling viral and inflammatory phases of disease. Neutralization of TGF-β, but not IL-10 or IL-4, significantly increased lung inflammatory monocytes and elevated serum but not lung IL-6. Neutralization of IL-4 prolonged weight loss and increased early perivascular infiltration without changing viral titer. Anti-IL-4 reduced expression of Arg1, a gene associated with alternative activation of macrophages. Neutralizing TGF-β and IL-4 had differential effects on pathology after virus control. Lung perivascular infiltration was reduced 7 dpi by neutralization of IL-4 or TGF-β, and periairway inflammation was affected by anti-TGF-β, while alveolar infiltrates were not affected by either. Anti-IL-4 prolonged IL-12 to 7 dpi along with reduced IL-10 in lungs. Overall, the immunoregulatory cytokines TGF-β and IL-4 dampen initial inflammation in this mouse-adapted SARS-CoV-2 infection, suggesting that promotion of immunoregulation could help patients in early stages of disease.
Keywords: IL-4; SARS-CoV-2; TGF-β; cytokines; immunoregulation.