The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.

/pdf/neurogenic-inflammation-after-traumatic-brain-injury-and-its-2zs5ifl0b3.pdf

Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation.

When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium a...

Origin and Consequences of Necroinflammation.

Paracetamol (acetaminophen) is the most commonly used over-the-counter (OTC) drug in the world. Despite its popularity and use for many years, the safety of its application and its mechanism of action are still unclear. Currently, it is believed that paracetamol is a multidirectional drug and at least several metabolic pathways are involved in its analgesic and antipyretic action. The mechanism of paracetamol action consists in inhibition of cyclooxygenases (COX-1, COX-2, and COX-3) and involvement in the endocannabinoid system and serotonergic pathways. Additionally, paracetamol influences transient receptor potential (TRP) channels and voltage-gated Kv7 potassium channels and inhibits T-type Cav3.2 calcium channels. It also exerts an impact on L-arginine in the nitric oxide (NO) synthesis pathway. However, not all of these effects have been clearly confirmed. Therefore, the aim of our paper was to summarize the current state of knowledge of the mechanism of paracetamol action with special attention to its safety concerns.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1440-1681.13392

Paracetamol - An old drug with new mechanisms of action.

The recruitment of neutrophils to sites of inflammation, their battle against invading microorganisms through phagocytosis and the release of antimicrobial agents is a highly coordinated and tightly regulated process that involves the interplay of many different receptors, ion channels and signalling pathways. Changes in intracellular calcium levels, caused by cytosolic Ca2+ store depletion and the influx of extracellular Ca2+ via ion channels, play a critical role in synchronizing neutrophil activation and function. In this review, we provide an overview of how Ca2+ signalling is initiated in neutrophils and how changes in intracellular Ca2+ levels modulate neutrophil function.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/eci.12964

Calcium signalling and related ion channels in neutrophil recruitment and function.

It is well known that certain active ingredients of the plants of Cannabis genus, i.e. the “phytocannabinoids” (pCB; e.g. (-)-trans-Δ9-tetrahydrocannabinol [THC], (-)-cannabidiol [CBD], etc.) can influence a wide array of biological processes, and the human body is able to produce endogenous analogues of these substances (“endocannabinoids” [eCB] e.g. arachidonoylethanolamine [anandamide, AEA], 2-arachidonoylglycerol [2-AG], etc.). These ligands, together with multiple receptors (e.g. CB1 and CB2 cannabinoid receptors, etc.), and a complex enzyme and transporter apparatus involved in the synthesis and degradation of the ligands constitute the endocannabinoid system (ECS), a recently emerging regulator of several physiological processes. The ECS is widely expressed in the human body, including several members of the innate and adaptive immune system, where eCBs, as well as several pCBs were shown to deeply influence immune functions thereby regulating inflammation, autoimmunity, anti-tumor, as well as anti-pathogen immune responses, etc. Based on this knowledge, many in vitro and in vivo studies aimed at exploiting the putative therapeutic potential of cannabinoid signaling in inflammation-accompanied diseases (e.g. multiple sclerosis) or in organ transplantation, and to dissect the complex immunological effects of medical and “recreational” marijuana consumption. Thus, the objective of the current article is (i) to summarize the most recent findings of the field; (ii) to highlight the putative therapeutic potential of targeting cannabinoid signaling; (iii) to identify open questions and key challenges; and (iv) to suggest promising future directions for cannabinoid-based drug development.

/pdf/targeting-cannabinoid-signaling-in-the-immune-system-high-ly-345qq9sdy3.pdf

Targeting Cannabinoid Signaling in the Immune System: "High"-ly Exciting Questions, Possibilities, and Challenges.

A complex network of many interacting mechanisms orchestrates immune and inflammatory responses. Among these, the cation channels of the transient receptor potential (TRP) family expressed by resident tissue cells, inflammatory and immune cells and distinct subsets of primary sensory neurons, have emerged as a novel and interrelated system to detect and respond to harmful agents. TRP channels, by means of their direct effect on the intracellular levels of cations and/or through the indirect modulation of a large series of intracellular pathways, orchestrate a range of cellular processes, such as cytokine production, cell differentiation and cytotoxicity. The contribution of TRP channels to the transition of inflammation and immune responses from a defensive early response to a chronic and pathological condition is also emerging as a possible underlying mechanism in various diseases. This review discusses the roles of TRP channels in inflammatory and immune cell function and provides an overview of the effects of inflammatory and immune TRP channels on the pathogenesis of human diseases.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13392

What is the evidence for the role of TRP channels in inflammatory and immune cells

Dupilumab for the treatment of recalcitrant eosinophilic dermatosis of haematologic malignancy

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What is the evidence for the role of TRP channels in inflammatory and immune cells

Dupilumab for the treatment of recalcitrant eosinophilic dermatosis of haematologic malignancy