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TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway

Rong Li^1,2, Jing Zhang³, Qiong Wang⁴

¹School of Optometry, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong. rong-rong.li@connect.polyu.hk.

Journal of Neuroinflammation

|October 14, 2022

Abstract

Background:

Microglia, the innate immune cells in the central nervous system, play an essential role in brain homeostasis, neuroinflammation and brain infections. Dysregulated microglia, on the other hand, are associated with neurodegenerative diseases, yet the mechanisms underlying pro-inflammatory gene expression in microglia are incompletely understood.

Methods:

We investigated the role of the actin-associated protein tropomyosin 1 (TPM1) in regulating pro-inflammatory phenotype of microglia in the retina by using a combination of cell culture, immunocytochemistry, Western blot, qPCR, TUNEL, RNA sequencing and electroretinogram analysis. TREM2^-/- mice were used to investigate whether TPM1 regulated pro-inflammatory responses downstream of TREM2. To conditionally deplete microglia, we backcrossed CX3CR1^CreER mice with Rosa26^iDTR mice to generate CX3CR1^CreER:Rosa26^iDTR mice.

Results:

We revealed a vital role for TPM1 in regulating pro-inflammatory phenotype of microglia. We found that TPM1 drove LPS-induced inflammation and neuronal death in the retina via the PKA/CREB pathway. TPM1 knockdown ameliorated LPS-induced inflammation in WT retinas yet exaggerated the inflammation in TREM2^-/- retinas. RNA sequencing revealed that genes associated with M1 microglia and A1 astrocytes were significantly downregulated in LPS-treated WT retinas but upregulated in LPS-treated TREM2^-/- retinas after TPM1 knockdown. Mechanistically, we demonstrated that CREB activated by TPM1 knockdown mediated anti-inflammatory genes in LPS-treated WT retinas but pro-inflammatory genes in LPS-treated TREM2^-/- retinas, suggesting a novel role for TREM2 as a brake on TPM1-mediated inflammation. Furthermore, we identified that TPM1 regulated inflammation downstream of TREM2 and in a microglia-dependent manner.

Conclusions:

We demonstrate that TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway. Our findings suggest that TPM1 could be a potential target for therapeutic intervention in brain diseases.

Insights

Tropomyosin 1 (TPM1) regulates microglial inflammation via the PKA/CREB pathway, acting downstream of TREM2. Targeting TPM1 offers a potential therapeutic strategy for neurodegenerative diseases.

Area of Science:

Neuroscience
Immunology
Cell Biology

Background:

Microglia are key innate immune cells in the central nervous system, crucial for brain health.
Dysfunctional microglia are implicated in neurodegenerative diseases, but mechanisms of pro-inflammatory gene expression remain unclear.

Purpose of the Study:

To investigate the role of tropomyosin 1 (TPM1) in regulating microglial pro-inflammatory responses.
To elucidate the signaling pathways and receptor interactions involved in TPM1-mediated microglial activation.

Main Methods:

Utilized cell culture, immunocytochemistry, Western blot, qPCR, TUNEL, RNA sequencing, and electroretinogram analysis.
Employed TREM2 knockout and CX3CR1-CreER/Rosa26-iDTR mice for conditional microglial depletion and TREM2 function studies.

Main Results:

TPM1 drives lipopolysaccharide (LPS)-induced retinal inflammation and neuronal death via the PKA/CREB pathway.
TPM1 knockdown reduced inflammation in wild-type retinas but exacerbated it in TREM2 knockout retinas.
TPM1 regulates inflammation downstream of TREM2 in a microglia-dependent manner, with CREB mediating differential gene expression.

Conclusions:

TPM1 mediates neuroinflammation downstream of TREM2 through the PKA/CREB signaling pathway.
TPM1 represents a potential therapeutic target for managing inflammatory brain diseases.

Read full analysis

Keywords:

CREB Inflammation Retina TREM2 Tropomyosin 1

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