Abstract
Inflammasomes are cytoplasmic inflammatory signaling protein complexes that detect microbial materials, sterile inflammatory insults, and certain host-derived elements. Inflammasomes, once activated, promote caspase-1–mediated maturation and secretion of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18, leading to pyroptosis. Current advances in inflammasome research support their involvement in the development of chronic inflammatory disorders in contrast to their role in regulating innate immunity. Cannabis (marijuana) is a natural product obtained from the Cannabis sativa plant, and pharmacologically active ingredients of the plant are referred to as cannabinoids. Cannabinoids and cannabis extracts have recently emerged as promising novel drugs for chronic medical conditions. Growing evidence indicates the potent anti-inflammatory potential of cannabinoids, especially Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and synthetic cannabinoids; however, the mechanisms remain unclear. Several attempts have been made to decipher the role of cannabinoids in modulating inflammasome signaling in the etiology of chronic inflammatory diseases. In this review, we discuss recently published evidence on the effect of cannabinoids on inflammasome signaling. We also discuss the contribution of various cannabinoids in human diseases concerning inflammasome regulation. Lastly, in the milieu of coronavirus disease-2019 (COVID-19) pandemic, we confer available evidence linking inflammasome activation to the pathophysiology of COVID-19 suggesting overall, the importance of cannabinoids as possible drugs to target inflammasome activation in or to support the treatment of a variety of human disorders including COVID-19.
Highlights
Animals, from lower vertebrates, such as hagfish, to higher ones, such as mammals, use innate, adaptive immune responses to protect themselves from external pathogens and injuries [1, 2]
Inflammasome amplification is regulated by ASC via three mechanisms: first, sensors nucleate ASC, forming oligomers and ASC nucleates caspase-1 such that the sensor, adaptor, and enzyme are always present at cumulative concentrations; second, cytokines formed by caspase-1 infiltrate immune cells, lowering their activation; third, “ASC specks” released after pyroptosis can be engulfed by neighboring cells, forming an inflammasome in recipient cells [70, 71]
It has been predicted that a caspase-11-bound pannexin-1–dependent decrease of intracellular K+ might activate the NLRP3 inflammasome [70], but further research is needed to understand whether the drop in intracellular K+ is sufficient to activate inflammasomes and/or whether other possible mechanisms are involved
Summary
From lower vertebrates, such as hagfish, to higher ones, such as mammals, use innate, adaptive immune responses to protect themselves from external pathogens and injuries [1, 2]. This type of DAMPmediated inflammatory response is often called “sterile inflammation” due to no pathogen involvement [5] Overall, both PAMPs and DAMPs can stimulate an initial immune response by activating different types of PRRs, including tolllike receptors (TLRs), nucleotide-binding domain (NBD) and leucine-rich-repeat-(LRR)-containing or nucleotidebinding and oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and several cytosolic DNA sensor-like receptors absent in melanoma 2 (AIM2)-like receptors (ALRs) [4, 6]. Cell death can result in the secretion of another round of inflammasome activators, such as uric acid and ATP, which both activate inflammasomes in a paracrine manner These signaling cascades eventually give rise to chronic inflammatory disorders, such as cardiovascular disease, cancer, metabolic disorders, autoimmune disorders, and neurodegenerative disorders [23]. Our goals in this review are to cover all published research on the action of cannabinoids on the inflammasome to propose the future therapeutic potential of cannabis in chronic inflammatory disorders
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