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Published on: December 26, 2016
Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease
Kimitoshi Kimura1,2,3,4, Ayshwarya Subramanian1,2,3,5, Zhuoran Yin1,2,3,6
1The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Abstract:
Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer's disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer's disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer's disease.
Insights
The immune-checkpoint TIM-3 (HAVCR2) maintains brain microglial homeostasis via TGFβ signaling. Deleting TIM-3 in microglia worsens Alzheimer's-like pathology but enhances phagocytosis, suggesting therapeutic potential.
Area of Science:
- Neuroimmunology
- Cellular Biology
- Neurodegenerative Diseases
Background:
- Microglia are key brain immune cells involved in neurodevelopment and neuroinflammation.
- TIM-3 (HAVCR2) is a genetic risk factor for Alzheimer's disease, but its role in microglia is unknown.
- Understanding microglial function is crucial for neurodegenerative disease research.
Purpose of the Study:
- To investigate the function of the immune-checkpoint molecule TIM-3 in microglia.
- To elucidate the mechanism by which TIM-3 influences microglial homeostasis and Alzheimer's disease pathology.
- To explore the therapeutic potential of targeting microglial TIM-3.
Main Methods:
- Utilized mouse models to study TIM-3 expression and function in microglia.
- Investigated the interaction of TIM-3 with TGFβ signaling pathway components (SMAD2, TGFBR2).
- Employed genetic deletion of Havcr2 in microglia and analyzed its effects on microglial phenotype, cognitive function, and amyloid-β pathology in 5×FAD mice.
- Conducted single-nucleus and single-cell RNA sequencing to analyze microglial gene expression.
Main Results:
- TGFβ signaling induces TIM-3 expression in microglia, which enhances TGFβ signaling to maintain microglial homeostasis.
- Genetic deletion of Havcr2 in microglia increases phagocytic activity and promotes a neurodegenerative microglial phenotype (MGnD/DAM).
- Microglia-specific deletion of Havcr2 ameliorates cognitive deficits and reduces amyloid-β pathology in a mouse model of Alzheimer's disease.
- Single-cell transcriptomics revealed a shift towards pro-phagocytic and anti-inflammatory gene expression in microglia lacking TIM-3.
Conclusions:
- TIM-3 plays a critical role in maintaining microglial homeostasis through interaction with the TGFβ signaling pathway.
- Targeting microglial TIM-3 presents a potential therapeutic strategy for Alzheimer's disease.
- Modulating TIM-3 in microglia impacts their phagocytic and inflammatory functions, influencing disease progression.
