Peroxisome Proliferator–Activated Receptor-δ Acts within Peripheral Myeloid Cells to Limit Th Cell Priming during Experimental Autoimmune Encephalomyelitis
| Autor: | Tracy L. McGaha, Tae Joon Yi, Rainer Akkermann, Marina Moshkova, Shannon E. Dunn, Jeeyoon Jennifer Ahn, Paulina C Drohomyrecky, Fei L Zhao, Ellinore R Doroshenko, Kalipada Pahan |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
CD4-Positive T-Lymphocytes
Adoptive cell transfer Encephalomyelitis Autoimmune Experimental Transgene Encephalomyelitis Immunology Receptors Cytoplasmic and Nuclear Peroxisome proliferator-activated receptor CD11c Mice Transgenic Biology Lymphocyte Activation Myelin oligodendrocyte glycoprotein Mice medicine Animals Immunology and Allergy Myeloid Cells Receptor Cells Cultured chemistry.chemical_classification CD11b Antigen Interleukin-12 Subunit p40 Experimental autoimmune encephalomyelitis Dendritic Cells Th1 Cells medicine.disease Adoptive Transfer Molecular biology Coculture Techniques Mice Inbred C57BL chemistry biology.protein Th17 Cells Myelin-Oligodendrocyte Glycoprotein |
| Zdroj: | The Journal of Immunology. 203:2588-2601 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1801200 |
| Popis: | Peroxisome proliferator-activated receptor (PPAR)-δ is a fatty acid–activated transcription factor that regulates metabolic homeostasis, cell growth, and differentiation. Previously, we reported that mice with a global deficiency of PPAR-δ develop an exacerbated course of experimental autoimmune encephalomyelitis (EAE), highlighting a role for this nuclear receptor in limiting the development of CNS inflammation. However, the cell-specific contribution of PPAR-δ to the more severe CNS inflammatory response remained unclear. In this study, we studied the specific involvement of PPAR-δ in myeloid cells during EAE using mice that had Cre-mediated excision of floxed Ppard driven by the lysozyme M (LysM) promoter (LysMCre:Ppardfl/fl). We observed that LysMCre:Ppardfl/fl mice were more susceptible to EAE and developed a more severe course of this disease compared with Ppardfl/fl controls. The more severe EAE in LysMCre:Ppardfl/fl mice was associated with an increased accumulation of pathogenic CD4+ T cells in the CNS and enhanced myelin-specific Th1 and Th17 responses in the periphery. Adoptive transfer EAE studies linked this EAE phenotype in LysMCre:Ppardfl/fl mice to heightened Th responses. Furthermore, studies using an in vitro CD11b+ cell:Th cell coculture system revealed that CD11b+CD11c+ dendritic cells (DC) from LysMCre:Ppardfl/fl mice had a heightened capacity to prime myelin oligodendrocyte glycoprotein (MOG)–specific Th cells compared with Ppardfl/fl counterparts; the effects of DC on Th1 cytokine production were mediated through production of the IL-12p40 homodimer. These studies revealed a role for PPAR-δ in DC in limiting Th cell priming during EAE. |
| Databáze: | OpenAIRE |
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