Abstract
Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel implicated in the nervous system as a key component of several inflammatory diseases. A massive amount of evidence has demonstrated that TRPV1 is extensively expressed in the central nervous system (CNS) and there might be a close relationship between TRPV1 and neuroinflammation, which is a crucial pathogenic factor in seizure generation, although it’s signaling mechanism has been less well characterized. Herein, we identified that TRPV1 is functionally expressed in the primary cultured mouse microglia and the membrane expression of TRPV1 is upregulated in rFS mice brain and specifically in activated microglia. Stimulation of TRPV1 promoted microglia activation and indirectly enhanced seizure susceptibility by inhibiting the neuroprotective effects of microglial transforming growth factor-beta1 (TGF-β1) via interaction with Toll-like receptor 4 (TLR4) in mice. Conversely, genetic deletion of TRPV1 alleviated hyperthermia or LPS-induced abnormal microglial activation and restored a balanced inflammatory microenvironment in the brain. Taken together, these findings show that microglial TRPV1, as a potential pro-inflammatory mediator, and participate in neuroinflammatory response, which will provide a novel therapeutic strategy for controlling the neuroinflammation-induced seizure.
Highlights
Transient receptor potential vanilloid type 1 (TRPV1) is a well-characterized, ligand-gated temperature-sensitive nonselective cationic channel that is activated by a wide variety of exogenous and endogenous factors, such as hyperthermia (>43◦C), capsaicin and certain biotoxins (Caterina et al, 1997; Bohlen et al, 2010)
The results indicated that TRPV1 contributes to the development of rFSs by inhibiting the M2 microglial activation through TGF-β1 signaling, which as a complementary pathway for M1 microglial activation to promote seizure
These findings indicate that the amount of colocalization between TRPV1 and Iba1 was weak in control mice, but the Pearson coefficient of correlation (PCC) for TRPV1 and Iba1 immunoreactive colocalization was moderate in rFS mice
Summary
Transient receptor potential vanilloid type 1 (TRPV1) is a well-characterized, ligand-gated temperature-sensitive nonselective cationic channel that is activated by a wide variety of exogenous and endogenous factors, such as hyperthermia (>43◦C), capsaicin and certain biotoxins (Caterina et al, 1997; Bohlen et al, 2010). Neurobehavioral studies have recently demonstrated that TRPV1 is broadly expressed in the brain (Hurtado-Zavala et al, 2017; Kong et al, 2017; Marrone et al, 2017) and critically implicated in neurological and mental disorders, such as epilepsy/seizure (Sun et al, 2013; Cho et al, 2018), anxiety, and neurodegenerative diseases (Edwards, 2014). Recent work has shown that TRPV1 is functionally expressed in a large proportion of microglia (Hassan et al, 2014; Miyake et al, 2015; Marrone et al, 2017) and modulates excitatory neurotransmission from microglia (Pascual et al, 2012; Marrone et al, 2017). TRPV1 mediates a series of transformations ranging from microglial cell death to inflammatory mediators (Kim et al, 2006; Hassan et al, 2014; Miyake et al, 2015; Marrone et al, 2017) under different stimulus conditions
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