Nuclear IL-33 restrains the early conversion of fibroblasts to an extracellular matrix-secreting phenotype
| Autor: | Nadine Frerker, Johanna Hol, Junbai Wang, Bjarte Fosby, Sobuj Mia, Francesca Gatti, Wojciech Pietka, Clara Hammarström, Guttorm Haraldsen, Olav Sundnes, Monika Kasprzycka |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Science IL1RL1 Kidney Article 03 medical and health sciences 0302 clinical medicine Fibrosis Renal fibrosis medicine Animals Fibroblast Cell Nucleus Multidisciplinary Chemistry Interleukin-6 Interleukins Fibroblasts medicine.disease Interleukin-33 Interleukin-1 Receptor-Like 1 Protein Cell biology Extracellular Matrix Interleukin 33 Mice Inbred C57BL Cell nucleus 030104 developmental biology medicine.anatomical_structure Cytokine Collagen Type III Phenotype 030220 oncology & carcinogenesis Medicine Chemokines Myofibroblast Intracellular |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Interleukin (IL)-33 is a cytokine that appears to mediate fibrosis by signaling via its receptor ST2 (IL-33R/IL1RL1). It is also, however, a protein that after synthesis is sorted to the cell nucleus, where it appears to affect chromatin folding. Here we describe a novel role for nuclear IL-33 in regulating the fibroblast phenotype in murine kidney fibrosis driven by unilateral ureteral obstruction. Transcriptional profiling of IL-33-deficient kidneys 24 h after ligation revealed enhanced expression of fibrogenic genes and enrichment of gene sets involved in extracellular matrix formation and remodeling. These changes relied on intracellular effects of IL-33, because they were not reproduced by treatment with a neutralizing antibody to IL-33 that prevents IL-33R/ST2L receptor signaling nor were they observed in IL-33R/ST2-deficient kidneys. To further explore the intracellular function of IL-33, we established transcription profiles of human fibroblasts, observing that knockdown of IL-33 skewed the transcription profile from an inflammatory towards a myofibroblast phenotype, reflected in higher levels of COL3A1, COL5A1 and transgelin protein, as well as lower expression levels of IL6, CXCL8, CLL7 and CCL8. In conclusion, our findings suggest that nuclear IL-33 in fibroblasts dampens the initial profibrotic response until persistent stimuli, as enforced by UUO, can override this protective mechanism. |
| Databáze: | OpenAIRE |
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