Targeting microglia-Th17 feed-forward loop to suppress autoimmune neuroinflammation
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Jun Xiao1,2, Zihan Meng1, Yao Lu1
1Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University, Tianjin, 300070, China.
Abstract:
Microglia and Th17 cells are the major immunopathogenic cells in multiple sclerosis and its animal model of immune aspects, experimental autoimmune encephalomyelitis (EAE). While studies have highlighted the distinct roles of microglia and Th17 cells in EAE, it remains unclear whether microglia, as potential professional antigen-presenting cells, activate and stabilize the effector program of EAE-pathogenic Th17 cells in vivo; and if so, whether the Th17 could in turn reinforce the active state of the microglia. Our data demonstrate in an array of mouse models, including active/passive-EAE and transgenic mice, a microglia-Th17 feed-forward activation loop drives EAE disease progression through a mechanism dependent on both MHC-II, proinflammatory cytokines, inflammatory chemokines as well as STING→NF-κB pathway in the microglia and effector cytokines produced by the pathogenic Th17 cells. We also captured and identified the molecular properties of the feed-forward loop, which are two-cell entities of microglia-Th17, and proved them as the functional units of antigen presentation and bi-directional activation between the two cell types. Moreover, ACT001, an orphan drug to treat glioblastoma, disrupts this feed-forward activation loop by inhibiting the STING→NF-κB pathway in microglia, thereby alleviating EAE. These findings emphasize the importance of interactions and bi-directional activations between microglia and Th17 in the autoimmune neuroinflammation, and provide rationale for further investigation on ACT001 as therapeutic option for autoimmune inflammatory diseases driven by similar mechanisms.
Insights
Microglia and T helper 17 (Th17) cells form a feed-forward loop driving experimental autoimmune encephalomyelitis (EAE). This interaction, targeted by drug ACT001, offers a new therapeutic strategy for autoimmune neuroinflammation.
Area of Science:
- Immunology
- Neuroscience
- Cell Biology
Background:
- Microglia and T helper 17 (Th17) cells are key players in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE).
- Distinct roles of microglia and Th17 cells in EAE are known, but their direct interaction and mutual activation in vivo remain unclear.
- The potential of microglia as antigen-presenting cells to activate and stabilize pathogenic Th17 cells requires investigation.
Purpose of the Study:
- To investigate the existence and mechanism of a microglia-Th17 feed-forward activation loop in EAE.
- To identify the molecular components and functional units of this proposed loop.
- To evaluate the therapeutic potential of ACT001 in disrupting this loop and alleviating EAE.
Main Methods:
- Utilized various mouse models, including active/passive EAE and transgenic mice.
- Analyzed the roles of MHC-II, proinflammatory cytokines, chemokines, and the STING→NF-κB pathway in microglia.
- Studied the contribution of effector cytokines from pathogenic Th17 cells.
Main Results:
- Demonstrated a microglia-Th17 feed-forward activation loop crucial for EAE progression.
- Identified microglia-Th17 two-cell entities as functional units for antigen presentation and bidirectional activation.
- Confirmed the dependence of this loop on MHC-II, cytokines, chemokines, and the STING→NF-κB pathway in microglia, as well as Th17 effector cytokines.
- Showed that ACT001 inhibits the STING→NF-κB pathway in microglia, disrupting the loop and reducing EAE severity.
Conclusions:
- The study reveals a critical microglia-Th17 feed-forward loop driving autoimmune neuroinflammation in EAE.
- Microglia-Th17 interactions are identified as functional units essential for disease pathogenesis.
- ACT001 demonstrates therapeutic potential by targeting this loop, suggesting broader applications for autoimmune diseases with similar mechanisms.
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