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Author Spotlight: Unveiling the Pathway Linking Obesity to Autoimmune Inflammation in Multiple Sclerosis
Published on: February 23, 2024
IFP35 family proteins promote neuroinflammation and multiple sclerosis
Xizhong Jing1, Yongjie Yao1, Danning Wu2
1School of Medicine, Sun Yat-sen University, Shenzhen 518107, China.
Abstract:
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.
Insights
Extracellular IFP35 family proteins, including IFP35 and NMI, drive neuroinflammation in multiple sclerosis (MS) by activating T cells and microglia. Targeting these proteins may offer new therapeutic strategies for MS.
Area of Science:
- Neuroimmunology
- Molecular and Cellular Biology
- Pathogenesis of Multiple Sclerosis
Background:
- Excessive T cell and microglia activation is central to multiple sclerosis (MS) pathogenesis.
- Regulatory molecules driving this overactivation in the central nervous system (CNS) are not fully understood.
- Extracellular IFP35 family proteins (IFP35, NMI) were previously identified as peripheral pro-inflammatory activators of macrophages.
Purpose of the Study:
- To investigate the role of IFP35 family proteins in neuroinflammation within the CNS and periphery.
- To identify novel molecular mechanisms contributing to the pathogenesis of multiple sclerosis.
Main Methods:
- Analysis of clinical transcriptomic data from MS patients.
- In vitro studies on cell activation and differentiation.
- Investigated the Toll-like receptor 4 (TLR4) pathway and nuclear factor kappa B (NF-κB) signaling.
- Utilized genetic knockout models (Nmi, Ifp35) and neutralizing antibodies in experimental autoimmune encephalomyelitis (EAE).
Main Results:
- IFP35 family protein expression is upregulated in MS patients.
- IFP35 and NMI activate microglia via TLR4/NF-κB pathway and activate dendritic cells.
- IFP35 and NMI promote naive T cell differentiation into Th1 and Th17 cells.
- Genetic deletion or antibody neutralization of IFP35/NMI reduced immune cell infiltration, demyelination, and EAE severity.
Conclusions:
- IFP35 family proteins are key mediators of neuroinflammation in MS.
- These proteins contribute to T cell and microglia overactivation, driving disease pathogenesis.
- IFP35 family proteins represent potential therapeutic targets for multiple sclerosis.
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