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CPEB1 regulates the inflammatory immune response, phagocytosis, and alternative polyadenylation in microglia
Maria P Ivshina1, Heleen M van 't Spijker1, Suna Jung1
1Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
Abstract:
Microglia are myeloid cells of the central nervous system that perform tasks essential for brain development, neural circuit homeostasis, and neural disease. Microglia react to inflammatory stimuli by upregulating inflammatory signaling through several different immune cell receptors such as the Toll-like receptor 4 (TLR4), which signals to several downstream effectors including transforming growth factor beta-activated kinase 1 (TAK1). Here, we show that TAK1 levels are regulated by CPEB1, a sequence-specific RNA binding protein that controls translation as well as RNA splicing and alternative poly(A) site selection in microglia. Lipopolysaccharide (LPS) binds the TLR4 receptor, which in CPEB1-deficient mice leads to elevated expression of ionized calcium binding adaptor molecule 1 (Iba1), a microglial protein that increases with inflammation, and increased levels of the cytokine IL6. This LPS-induced IL6 response is blocked by inhibitors of JNK, p38, ERK, NFκB, and TAK1. In contrast, phagocytosis, which is elevated in CPEB1-deficient microglia, is unaffected by LPS treatment or ERK inhibition, but is blocked by TAK1 inhibition. These data indicate that CPEB1 regulates microglial inflammatory responses and phagocytosis. RNA-seq indicates that these changes in inflammation and phagocytosis are accompanied by changes in RNA levels, splicing, and alternative poly(A) site selection. Thus, CPEB1 regulation of RNA expression plays a role in microglial function.
Insights
The RNA binding protein CPEB1 regulates microglial inflammatory responses and phagocytosis by controlling RNA expression. Loss of CPEB1 in microglia leads to altered inflammatory signaling and phagocytic activity.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia are key myeloid cells in the central nervous system, vital for brain development, homeostasis, and disease.
- Microglia activate inflammatory signaling via receptors like Toll-like receptor 4 (TLR4), engaging effectors such as transforming growth factor beta-activated kinase 1 (TAK1).
Purpose of the Study:
- To investigate the role of CPEB1, an RNA binding protein, in regulating microglial inflammatory responses and phagocytosis.
- To elucidate the mechanisms by which CPEB1 influences microglial function at the RNA expression level.
Main Methods:
- Utilized CPEB1-deficient mice to study microglial responses to lipopolysaccharide (LPS) stimulation.
- Employed RNA-sequencing (RNA-seq) to analyze changes in RNA levels, splicing, and polyadenylation.
- Assessed inflammatory markers (Iba1, IL6) and phagocytosis in microglia.
Main Results:
- CPEB1 deficiency in microglia resulted in elevated ionized calcium binding adaptor molecule 1 (Iba1) and interleukin 6 (IL6) upon LPS stimulation.
- The LPS-induced IL6 response was dependent on TAK1 and other signaling pathways (JNK, p38, ERK, NFκB).
- Phagocytosis, while elevated in CPEB1-deficient microglia, was specifically inhibited by TAK1 inhibition, not LPS or ERK inhibition.
Conclusions:
- CPEB1 plays a critical role in modulating microglial inflammatory signaling and phagocytic capacity.
- CPEB1 regulates microglial function through control of RNA processing, including translation, splicing, and polyadenylation.
- These findings highlight CPEB1 as a key regulator of microglial immune responses in the brain.
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