Table 1.
Role of major Inflammasomes in the representative chronic inflammatory disorders along with known cannabinoid effect.
| Disorder | Inflammasomes | Pathophysiology | Genetic variations involved? | Possible reported effect of cannabis |
|---|---|---|---|---|
| Addison’s disease | NLRP1 | Increased risk of autoimmunity | Yes (98) | A case report of Cannabis use disorder contributing to Addison’s (99) |
| Skin inflammation and cancer | NLRP1 | Highly expressed in the skin; mutations in NLRP1 cause its self-oligomerization and atypical activation leading to various skin inflammatory conditions (100, 101) | Yes (100) | Anti-inflammatory, antipruritic, anti-aging, and anti-cancerous properties of cannabinoids along with mechanisms reviewed in details (102) |
| NLRP3 | NLRP3-dependent production of IL-1β may promote skin cancers | Yes (103, 104) | ||
| AIM2 | AIM2 upregulation in acute and chronic skin inflammatory conditions and cancer (105, 106) | No | ||
| Inflammatory bowel disease (IBD) | NLRP1 | NLRP1 decreases the growth of beneficial gut bacteria promoting IBD (107) | No | Antioxidant and anti-inflammatory effects of cannabinoids on IBD reviewed in details (108) |
| NLRP3 | NLRP3 activation promotes IBD and not crucial for intestinal barrier maintenance (109) | Yes (110) | ||
| AIM2 | AIM2 is an crucial regulator of intestinal inflammation via the IL-18/IL-22/STAT3 pathway (111) | No | ||
| Systemic lupus erythematosus (SLE) | NLRP1 | Upregulation of NLRP1 gene leading to higher IL-1β levels in SLE patients (112) | Yes (113) | Cannabidiol is not beneficial in the murine model of SLE (114), however, ajulemic acid (selective CB2 agonist) is highly beneficial; undergoing clinical trials (115). |
| NLRP3 | NLRP3 activation is involved in the differentiation of Th17 cells SLE mice (116) | Yes (112) | ||
| AIM2 | AIM2 acts as na apoptotic DNA sensor in SLE causing macrophage activation (117) | No | ||
| Type-1 diabetes (T1D) | NLRP1 | Protective and detrimental role of NLRP1 variants depending on different ethnic population (118, 119) | Yes (113) | Increased risk of diabetic ketoacidosis (DKA) in type-1 diabetics who are moderate cannabis users (120) but cannabidiol treatment improves depression- and anxiety-like behavior in experimental type-1 diabetes in mice (121) |
| NLRP3 | NLRP3 is crucial for the expression of the chemokine receptors in T-cells regulating chemotaxis of immune cells in T1D mice (122) | Yes (123) | ||
| AIM2 | AIM2 protects against T1D by reducing pancreatic pro-inflammatory response via IL-18 (124) | No | ||
| Type-2 diabetes (T2D) | NLRP3 | NLRP3-mediated IL-1β and IL-18 release and pyroptosis worsen insulin resistance and the progression of T2D, reviewed here (125). The activation of NLRP3 is upregulated in T2D patients (126) | Yes (127) | Chronic cannabis use was associated with visceral adiposity and insulin resistance in the adipose tissue (128), however, lifetime marijuana use showed lower insulin resistance in obese but not in non-obese adults (129). |
| AIM2 | Cell-free mitochondrial DNA activates AIM2 leading to Il-1β and IL-18-mediated inflammation in T2D patients (130) and AIM2 inhibition improved cardiac function in a diabetic rat model by blocking caspase-1 activity (131) | No | ||
| NLRC4 | NLRC4 is a major contributor of IL-1β release in renal tissues contributing to the diabetic nephropathy (132) | Yes (133) | ||
| Rheumatoid Arthritis (RA) | NLRP1 | Inhibition of NLRP1 in arthritis model of mice significantly inhibited synovial inflammation (134) | Yes (98) | Cannabinoids are helpful in reducing pain and inflammation with RA via different mechanisms of action, reviewed here (135). |
| NLRP3 | Inhibition of NLRP3 in murine model of arthritis reduced the production of interleukin IL-1β and reduced inflammation of joints (136) and human patients with active RA showed higher expression and activation of NLRP3 (137) | Yes (137) | ||
| AIM2 | Self-DNA sensed by AIM2 drives autoinflammation in mice with chronic polyarthritis mimicking RA in humans (138) | No | ||
| Alzheimer’s disease (AD) | NLRP1 | NLRP1 is involved in the neuroinflammation via IL-1β and IL-18-dependent neuronal pyroptosis along with NLRP1–caspase1–caspase6-mediated axonal degeneration and neuroinflammation leading to neuronal death (139). AD patients showed higher NLRP1 activation as well (140). | Yes (141) | Various studies, reviewed here (142), found limited evidence of the effectiveness of medical cannabis in neuropsychiatric symptoms associated with dementia. A well-structured randomized controlled trial (RCT) is needed to prove the clinical efficacy of medical cannabis in AD. However, cannabidiol, via multiple cannabinoid receptor independent mechanisms showed a positive impact on the progression of AD (143). |
| NLRP3 | NLRP3 is upregulated in an animal model of AD causing IFN1β production by microglia and inhibition of NLRP3 reduced the deposition of amyloid-β (140). AD patients exhibited NLRP3 inflammasome assembly and activation with high amounts of IL-1β and IL-18 (140). | Yes (144) | ||
| AIM2 | Increased cytosolic DNA in traumatic brain injury detected by immune cells to activate AIM2 inflammasome and IL-1β and IL-18-dependent neuronal pyroptosis contributing to neurodegeneration in the pathogenesis of AD (145). | No | ||
| NLRC4 | NLRC4 inflammasome, via IL-1β and IL-18, contributes to memory impairment and neuroinflammation in a rat model of Alzheimer-like disease (146). | No | ||
| Parkinson’s disease (PD) | NLRP1 | NLRP1 has been indirectly linked to PD by contributing to neuroinflammation and axonal degeneration via the caspase-1-caspase-6-mediated IL-1β pathway (147). | No | A systematic review found insufficient evidence to recommend the use of medical cannabinoids for motor symptoms in PD (148). A well-designed RCT is needed, however, cannabidiol has shown great potential as a prototype for drug development for PD (143). |
| NLRP3 | Several studies implicate a pathogenic role of NLRP3 in PD via IL-1β and IL-18-dependent pyroptosis. α-Synuclein activates TLR2 and TLR4-mediated NLRP3 inflammasome assembly and caspase-1 maturation both (149). | Rare NLRP3 polymorphism decreased the risk of PD (150) | ||
| AIM2 | AIM2 inflammasome activity was augmented by inhibition of Parkinson’s disease-associated mitochondrial serine protease (151). | No | ||
| NLRC4 | NLRC4 is crucial in regulating inflammation in aging (Inflammaging) which contributes to the development of neurodegenerative diseases like PD (152). | No | ||
| Cardiovascular disorders (CVDs) | NLRP1 | NLRP1 gene expression was found to be significantly higher in the patients with aortic occlusive disease (AOD) (153) and coronary stenosis (154) suggesting its importance in the development of atherosclerosis. | Yes (155) | Although marijuana use has been positively correlated with the increased risk of CVDs (156), several studies suggested the cardioprotective role of cannabidiol (157); suggesting a need for further research. |
| NLRP3 | NLRP3 has been implicated in multiple CVDs and inhibition of NLRP3 holds great potential for treating such disorders (109). | Yes, coronary artery disease (158) | ||
| AIM2 | AIM2 hyper-activation is reported in a variety of CVDs including myocardial infarction (159) and atherosclerosis (160) | No | ||
| NLRC4 | NLRC4 is involved in the pathophysiology of atherosclerosis (154) and myocardial infarction (159). | Yes (161) | ||
| Cancers | NLR family | NLRP1, NLRP3, NLRC4, NLRP6, NLRP7, and NLRP12 have mixed roles in the pathogenesis of a variety of cancers as reviewed here in details (162, 163). | Yes (163) | Medical cannabis could be prescribed for nausea and vomiting after chemotherapy (14) but there is a weak evidence for their clinical efficacy in the management of cancer pain and other symptoms (164). RCTs are needed, however, non-THC cannabinoids show promising anti-cancerous actions (165). |
| AIM2 | Upregulation of AIM2 in oral, cervical, and lung cancer and downregulation in colorectal and small bowel cancer (166) | Yes (167) |