TRPA1 Role in Inflammatory Disorders: What Is Known So Far?

Landini, Lorenzo; Araújo, Daniel Souza Monteiro de; Titiz, Mustafa; Geppetti, Pierangelo; Nassini, Romina; Logu, Francesco De

doi:10.3390/ijms23094529

Cited by 23 publications

(29 citation statements)

References 200 publications

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“…These findings reveal that the role of IL-1β in host defense is complex and pleiotropic because it is both a pro-inflammatory mediator capable of causing tissue injury, and an anti-inflammatory signal via vagus TRPA1-dependent suppression of pro-inflammatory cytokine production which reduces collateral damage. Similarly, abundant prior work has implicated a key role of TRPA1 in inflammation, pain, itch, and as a sensor of inflammatory mediators, cellular stress, and tissue damage (Bautista et al 2013 ; Viana 2016 ; Silverman et al 2020 ; Landini, et al 2022 ). The present data now reveal the role of TRPA1 as also pleiotropic in mediating protective, homeostatic mechanisms in inflammation and infection because the results indicate an important role for vagus nerve TRPA1 ion channels in activating the thermoregulatory responses to IL-1β.…”

Section: Discussionmentioning

confidence: 95%

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses

Silverman

Tynan²,

Hepler³

et al. 2023

Mol Med

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Background Inflammation, the physiological response to infection and injury, is coordinated by the immune and nervous systems. Interleukin-1β (IL-1β) and other cytokines produced during inflammatory responses activate sensory neurons (nociceptors) to mediate the onset of pain, sickness behavior, and metabolic responses. Although nociceptors expressing Transient Receptor Potential Ankyrin-1 (TRPA1) can initiate inflammation, comparatively little is known about the role of TRPA1 nociceptors in the physiological responses to specific cytokines. Methods To monitor body temperature in conscious and unrestrained mice, telemetry probes were implanted into peritoneal cavity of mice. Using transgenic and tissue specific knockouts and chemogenetic techniques, we recorded temperature responses to the potent pro-inflammatory cytokine IL-1β. Using calcium imaging, whole cell patch clamping and whole nerve recordings, we investigated the role of TRPA1 during IL-1β-mediated neuronal activation. Mouse models of acute endotoxemia and sepsis were used to elucidate how specific activation, with optogenetics and chemogenetics, or ablation of TRPA1 neurons can affect the outcomes of inflammatory insults. All statistical tests were performed with GraphPad Prism 9 software and for all analyses, P ≤ 0.05 was considered statistically significant. Results Here, we describe a previously unrecognized mechanism by which IL-1β activates afferent vagus nerve fibers to trigger hypothermia, a response which is abolished by selective silencing of neuronal TRPA1. Afferent vagus nerve TRPA1 signaling also inhibits endotoxin-stimulated cytokine storm and significantly reduces the lethality of bacterial sepsis. Conclusion Thus, IL-1β activates TRPA1 vagus nerve signaling in the afferent arm of a reflex anti-inflammatory response which inhibits cytokine release, induces hypothermia, and reduces the mortality of infection. This discovery establishes that TRPA1, an ion channel known previously as a pro-inflammatory detector of cold, pain, itch, and a wide variety of noxious molecules, also plays a specific anti-inflammatory role via activating reflex anti-inflammatory activity.

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Section: Discussionmentioning

confidence: 95%

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses

Silverman

Tynan²,

Hepler³

et al. 2023

Mol Med

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“…As a member of the TRP subfamily of channels, the TRPA1 is largely concentrated in a subpopulation of primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia, where its activation promotes neurogenic inflammatory responses ( 83 ). TRPA1 detects pro-inflammatory molecules.…”

Section: Effect Of Trp Channels On the Anti-inflammatory Effect Of Me...mentioning

confidence: 99%

“…TRPA1 detects pro-inflammatory molecules. Meanwhile, it can also be activated by endogenous pro-inflammatory molecules in several inflammatory diseases, including asthma, rheumatoid arthritis, and dermatitis ( 83 , 84 ). In terms of the activation of TRPA1 in murine by menthol, submicromolar to low-micromolar menthol doses activate heterologously produced TRPA1 channels, while greater amounts block them ( 85 – 87 ).…”

Section: Effect Of Trp Channels On the Anti-inflammatory Effect Of Me...mentioning

confidence: 99%

Cold stimuli, hot topic: An updated review on the biological activity of menthol in relation to inflammation

Cheng

Xu²

2022

Front. Immunol.

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BackgroundRising incidence of inflammation-related diseases is an increasing concern nowadays. However, while menthol is a wildly-used and efficacious complementary medicine, its pharmacological mechanism still remains uncertain. Superimposed upon that, the aim of this review is to summarize the contemporary evidence of menthol’s anti-inflammatory activity.MethodsUsing the pharmacopeias and electronic databases, including Web of Science, PubMed, and CNKI, this study analyzed the relevant research articles and review articles from 2002 to 2022 and concluded those results and conjectures to finish this article.ResultsThe decrease in pro-inflammatory cytokines and related inflammatory markers, as well as associated pathway activation, was found to play the greatest role in the protective effects of menthol against inflammatory damage or association with protection against chronic inflammation.ConclusionThis review mainly concludes the progress in menthol’s anti-inflammatory activity. Further studies are needed to establish relationships between the mechanisms of action and to clarify the clinical relevance of any anti-inflammatory effects.

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“…TRPM8 is activated by cooling, menthol, and other chemicals that produce a cooling sensation ( McKemy et al, 2002 ; Peier et al, 2002a ; Yin and Lee, 2020 ). TRPA1, the “wasabi receptor,” is a promiscuous damage sensing receptor that is activated by noxious pungent compounds in radishes, mustard, and garlic, as well as reactive oxygen species produced during tissue stress ( Bautista et al, 2005 ; Takahashi et al, 2008 ; Manolache et al, 2021 ; Kashio and Tominaga, 2022 ; Landini et al, 2022 ). In rodents, these TRP channels are expressed in somatosensory neurons; however, several are also reported to be expressed in epithelial cells, including the oral epithelium ( Wang et al, 2011 ; Vandewauw et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Localization of TRP Channels in Healthy Oral Mucosa from Human Donors

Moayedi

Michlig

Park

et al. 2022

eNeuro

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The oral cavity is exposed to a remarkable range of noxious and innocuous conditions, including temperature fluctuations, mechanical forces, inflammation, and environmental and endogenous chemicals. How such changes in the oral environment are sensed is not completely understood. Transient receptor potential (TRP) ion channels are a diverse family of molecular receptors that are activated by chemicals, temperature changes, and tissue damage. In non-neuronal cells, TRP channels play roles in inflammation, tissue development, and maintenance. In somatosensory neurons, TRP channels mediate nociception, thermosensation, and chemosensation. To assess whether TRP channels might be involved in environmental sensing in the human oral cavity, we investigated their distribution in human tongue and hard palate biopsies. TRPV3 and TRPV4 were expressed in epithelial cells with inverse expression patterns where they likely contribute to epithelial development and integrity. TRPA1 immunoreactivity was present in fibroblasts, immune cells, and neuronal afferents, consistent with known roles of TRPA1 in sensory transduction and response to damage and inflammation. TRPM8 immunoreactivity was found in lamina propria and neuronal subpopulations including within the end bulbs of Krause, consistent with a role in thermal sensation. TRPV1 immunoreactivity was identified in intraepithelial nerve fibers and end bulbs of Krause, consistent with roles in nociception and thermosensation. TRPM8 and TRPV1 immunoreactivity in end bulbs of Krause suggest that these structures contain a variety of neuronal afferents, including those that mediate nociception, thermosensation, and mechanotransduction. Collectively, these studies support the role of TRP channels in oral environmental surveillance and response.

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TRPA1 Role in Inflammatory Disorders: What Is Known So Far?

Cited by 23 publications

References 200 publications

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1β induced hypothermia and reflex anti-inflammatory responses

Cold stimuli, hot topic: An updated review on the biological activity of menthol in relation to inflammation

Localization of TRP Channels in Healthy Oral Mucosa from Human Donors

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