"TRP inflammation" relationship in cardiovascular system

Abstract

Despite considerable advances in the research and treatment, the precise relationship between inflammation and cardiovascular (CV) disease remains incompletely understood. Therefore, understanding the immunoinflammatory processes underlying the initiation, progression, and exacerbation of many cardiovascular diseases is of prime importance. The innate immune system has an ancient origin and is well conserved across species. Its activation occurs in response to pathogens or tissue injury. Recent studies suggest that altered ionic balance, and production of noxious gaseous mediators link to immune and inflammatory responses with altered ion channel expression and function. Among plausible candidates for this are transient receptor potential (TRP) channels that function as polymodal sensors and scaffolding proteins involved in many physiological and pathological processes. In this review, we will first focus on the relevance of TRP channel to both exogenous and endogenous factors related to innate immune response and transcription factors related to sustained inflammatory status. The emerging role of inflammasome to regulate innate immunity and its possible connection to TRP channels will also be discussed. Secondly, we will discuss about the linkage of TRP channels to inflammatory CV diseases, from a viewpoint of inflammation in a general sense which is not restricted to the innate immunity. These knowledge may serve to provide new insights into the pathogenesis of various inflammatory CV diseases and their novel therapeutic strategies.

Keywords: Cardiovascular; Disease; Inflammasome; Inflammation; Innate immune system; TRP.

Fig. 1

Factors affecting innate immune response via TRP channels. An incoming microorganism or virus infection can induce inflammasome activation by stimulating innate immune receptors, such as Toll-like receptors (TLRs). Alternatively, TRP channel can be activated by the constituents of microorganism (e.g., LPS) directly or indirectly through TLR activation. TRP channel is also activated by potentially toxic/harmful environmental factors, such as MSU, silica, Alum, Aβ, and PM. In addition, an essential nutrient and a cellular constituent cholesterol can modulate TRP channel activity. Abnormal TRP channel activity causes Ca²⁺ influx and thereby produces ROS. The resultant intracellular Ca²⁺ elevation and ROS may induce inflammasome activity. Moreover, dysfunction of TRP channel in mitochondria or lysosome can also activate inflammasome. It should be noted that appropriate operation of autophagy is essential to suppress the caspase-1 activity, which would prevent the production of inflammatory cytokine (IL-1β and IL-18). How TRP channel-mediated Ca²⁺ influx regulates the inflammasome activation is not fully understood; but quite conceivably, it would play a key role in innate immune response. Question marks denote the hypothetical pathways that will require further proof

Fig. 2

Possible link of TRP channels to persistent inflammasome activation. Inflammation are mediated by signal transduction from both inflammation-related receptors and stress-sensing TRP channels to transcription factors. The “Receptor” pathway is activated via alteration of internal or external environmental factors in affected cells, including abnormal upregulation or persistent activation of receptors (e.g., cytokine receptors, growth factor receptors, Toll-like receptors) with increased kinase activity, excessive ROS production, and intracellular Ca²⁺ perturbation. The “TRP” pathway can also be activated by alteration of internal or external environmental factors and is susceptible to the regulations at functional and expression levels. Importantly, both pathways may intersect to modulate each other, since many of the environmental factors associated with inflammation are physical and chemical cell-stressing stimuli. Besides being involved in proliferation, survival, migration, and differentiation, transcription factors can induce the expression of many proinflammatory cytokines and other inflammatory mediators. Importantly, the receptors for many of these cytokines, chemokines, and mediators can further activate the inflammatory transcription factors, thereby forming autocrine and paracrine feedback loops. This would then result in the continuous amplification and promotion of inflammatory reactions leading to chronic inflammation