Phenylbutyrate facilitates homeostasis of non-resolving inflammatory macrophages
| Autor: | Liwu Li, Allison Rahtes, Kisha Pradhan, Chang Lu, Mimosa Sarma, David Xie |
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| Rok vydání: | 2019 |
| Předmět: |
Special Issue Articles
Lipopolysaccharides lcsh:Immunologic diseases. Allergy 0301 basic medicine LPS NF-E2-Related Factor 2 Immunology Macrophage polarization Butylamines Microbiology Phenylbutyrate Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine NFR2 Animals Homeostasis Medicine Cation Transport Proteins Molecular Biology Cells Cultured Chemokine CCL2 Inflammation Thesaurus (information retrieval) business.industry Innate polarization Macrophages p62 Ubiquitination Cell Differentiation Cell Biology 4-PBA Phenylbutyrates Cell biology Mice Inbred C57BL 030104 developmental biology Infectious Diseases Gene Expression Regulation lcsh:RC581-607 business Transcription Factor TFIIH 030215 immunology |
| Zdroj: | Innate Immunity, Vol 26 (2020) Innate Immunity |
| ISSN: | 1753-4267 1753-4259 |
| Popis: | Non-resolving inflammatory monocytes/macrophages are critically involved in the pathogenesis of chronic inflammatory diseases. However, mechanisms of macrophage polarization are not well understood, thus hindering the development of effective strategies to promote inflammation resolution. In this study, we report that macrophages polarized by subclinical super-low dose LPS preferentially expressed pro-inflammatory mediators such as ccl2 (which encodes the protein monocyte chemo attractant protein-1) with reduced expression of anti-inflammatory/homeostatic mediators such as slc40a1 (which encodes the protein ferroportin-1). We observed significantly elevated levels of the autophagy-associated and pro-inflammatory protein p62 in polarized macrophages, closely correlated with the inflammatory activation of ccl2 gene expression. In contrast, we noted a significant increase of ubiquitinated/inactive nuclear-erythroid-related factor 2 (NRF2), consistent with reduced slc40a1 gene expression in polarized macrophages. Addition of the homeostatic restorative agent phenylbutyrate (4-PBA) effectively reduced cellular levels of p62 as well as ccl2 gene induction by super-low dose LPS. On the other hand, application of 4-PBA also blocked the accumulation of ubiquitinated NRF2 and restored anti-inflammatory slc40a1 gene expression in macrophages. Together, our study provides novel insights with regard to macrophage polarization and reveals 4-PBA as a promising molecule in restoring macrophage homeostasis. |
| Databáze: | OpenAIRE |
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