IFP35 family proteins promote neuroinflammation and multiple sclerosis
Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B-dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi-/- , Ifp35-/- , or administration of neutralizing antibodies against IFP35 alleviated the immune cells' infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:118 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 118(2021), 32 vom: 10. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jing, Xizhong [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.12.2021 Date Revised 26.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2102642118 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM329071092 |
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| 245 | 1 | 0 | |a IFP35 family proteins promote neuroinflammation and multiple sclerosis |
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| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B-dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi-/- , Ifp35-/- , or administration of neutralizing antibodies against IFP35 alleviated the immune cells' infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DAMP | |
| 650 | 4 | |a T cell activation | |
| 650 | 4 | |a microglia activation | |
| 650 | 4 | |a multiple sclerosis | |
| 650 | 4 | |a neuroinflammation | |
| 650 | 7 | |a Antibodies, Neutralizing |2 NLM | |
| 650 | 7 | |a IFI35 protein, human |2 NLM | |
| 650 | 7 | |a IFP35 protein, mouse |2 NLM | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Lysophosphatidylcholines |2 NLM | |
| 650 | 7 | |a NMI protein, human |2 NLM | |
| 650 | 7 | |a NMI protein, mouse |2 NLM | |
| 700 | 1 | |a Yao, Yongjie |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Danning |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Xu |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Na |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yingfang |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Huanhuan |e verfasserin |4 aut | |
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