الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 32 |  |  |
| | | from | 32 | | |
Abstract
Inflammasomes have been linked to a variety of autoinflammatory and autoimmune diseases, including neurodegenerative diseases (multiple sclerosis, Alzheimer’s disease and Parkinson’s disease) and metabolic disorders (atherosclerosis, type 2 diabetes and obesity). In the initiation of inflammatory disease, inflammasomes play either causative or contributing roles, and also exaggerate the pathology in response to host-derived factors (Strowig et al., 2012).
Active caspase-1 is a cysteine-dependent protease that cleaves the precursor cytokines pro-IL-1β and pro-IL-18, generating the biologically active cytokines IL-1β and IL-18, respectively. Active caspase-1 is also able to induce an inflammatory form of cell death known as pyroptosis (Lamkanfi & Dixit, 2014).
Four inflammasome complexes have been described to date. The most intensely studied is NLRP3. Other inflammasomes described include the NLRP1 inflammasome (activated by bacterial ligands such as MDP or anthrax toxin) and the NLRP4 (also known as Ipaf) inflammasome (activated by flagellins). Finally, AIM2, which is not an NLR but a member of the PYHIN family of proteins, can form an inflammasome that can be activated by intracytoplasmic DNA (Ozaki et al., 2015).
Mechanism of action of inflammasome includes proteolytic Maturation of proIL-1β and proIL-18, Pyroptosis and Cytokine production (Vanaja et al., 2015).
The inflammasome most studied is the NLRP3-inflammasome since it can be activated by a large variety of PAMPs, DAMPs, (ROS), proteases released into the cytosol by lysosomal damage caused by
amyloid-β, silica, asbestos, MSU, uric acid, cathepsin B or cholesterol crystals, or potassium efflux from the cell (Lamkanfi & Dixit, 2014).
Some common conditions, such as gout, type 2 diabetes and even atherosclerosis are also included among the diseases in which the NLRP3 inflammasome may play a role. Furthermore, hereditary mutations of pyrin and PSTPIP1 result in NLRP3-independent IL-1b secretion, leading to Familial Mediterranean Fever (FMF) and the PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne syndrome), respectively (Yang et al., 2013).
NLRP1 is a candidate gene for a group of autoimmune diseases including vitiligo, autoimmune thyroid disease, type 2 diabetes, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus and Addison’s disease (Lissner and Siegmund, 2011).
The NLRC4/ Ipaf is important for caspase-1 activation in response to (gram-negative bacteria possessing type III or IV secretion systems) salmonella, pseudomonas, legionella, listeria, anaplasma and shigella (Schroder et al., 2012).
The AIM2 Inflammasome is the first identification of a non-NLR family member forming an inflammasome scaffold, and oligomerization of the complex (Hornung et al., 2009).
Autoinflammatory diseases are illnesses caused by primary dysfunction of the innate immune system. Proteins that are mutated in Autoinflammatory diseases mediate the regulation of NFkB activation, cell apoptosis, and IL-1β secretion through cross-regulated and sometimes common signaling pathways. Autoinflammatory diseases include a broad number of monogenic [e.g., familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), mevalonate
kinase deficiency (MKD), tumor necrosis factor (TNF)-receptor-associated periodic syndrome (TRAPS)] and multifactorial (e.g., Behcet’s syndrome) disorders (Latz et al., 2013).
Chronic inflammation and recruitment of macrophages has been recognized as a hallmark of obesity for decades. Recent work indicates that innate and adaptive immune processes in adipose tissue play central roles in the development of obesity-induced inflammatory responses and indicates potential roles for NLRP3 inflammasome activity in these processes (Yu et al., 2011).
Aberrant activation of the innate immune system in metabolic disorders such as type 2 diabetes has been recognized to be an important mechanism of disease pathogenesis. Emergence of a chronic proinflammatory state driven by the activation of myeloid lineage innate immune cells, such as macrophages and neutrophils, has been directly linked to the emergence of insulin resistance (Grateau and Duruo, 2010).
In atherosclerosis, cholesterol crystals in atherosclerotic lesions activate the NLRP3 infammasome in macrophages, leading to inflammation and cell infiltration. This amplified inflammatory cascade leads to the accumulation of extracellular lipids, resulting in cell injury and/or death and increased atherosclerosis progression (Higa et al., 2013).
MSU crystals induce the production of inflammatory cytokines from monocytes and macrophages, particularly IL-1β, but do not induce IL-1β production in macrophages with ablations of various NLRP3 inflammasome. Studies show that crystals of monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD), the causative agents of gout and pseudogout, respectively (Manoranjan et al., 2011).
Liver expression of NLRP3 inflammasome genes, caspase-1 activity, and mature IL-1β is, however, dramatically increased in mouse models of NASH. NAFLD, the precursor to NASH, is also characterized by a marked increase in hepatocyte lipid accumulation (steatosis), which is attenuated by genetic ablation of NLRP3 inflammasome components (Gomesa et al., 2015).
Some roles of the inflammasome in kidney disease have been well reviewed in the context of acute kidney injury/chronic kidney disease and kidney inflammation and fibrosis (Lorenz et al., 2013).
NLRP3 inflammasome is involved in the pathogenesis of the chronic airway inflammation in COPD, since increased levels of several activators of NLRP3 are present in the airways and lungs of patients with COPD (Franchi et al., 2006).
Several lines of evidence suggest that inflammasomes, and particularly the NLRP3 inflammasome, might be involved in the pathogenesis of fibrosing lung diseases, including idiopathic pulmonary fibrosis and diseases elicited by known environmental exposures (e.g. asbestosis and silicosis) (Bryan et al., 2009).
Alzheimer’s disease is a neurodegenerative, progressive and chronic disease characterized by deposition of misfolded protein amyloid-β in the brain and elevated inflammatory cytokines, such as TNF-α, IFN-γ and interleukins (Ozaki et al., 2015).
Inflammasome-mediated cell death, or pyroptosis, also appears to be involved in oncogenesis, since dysregulation of pyroptosis is tightly associated with tumor progression. chronic inflammation is often linked with increased cancer risk, and proinflammatory cytokines are frequently associated with tumor progression (Vladimer et al., 2014).
Given the important role of the infammasome in intestinal
immunity, it is not surprising that a large number of studies have examined the potential role of the inflammasome in the development and pathogenesis of inflammatory bowel disease (IBD) (Jabaut et al., 2013).
IL-1 inhibition has been highly effective not only in IL-1 mediated disorders like CAPS or DIRA, but also in metabolic disorders such as gout or diabetes and in genetically complex autoinflammatory disorders like Behcet’s disease (Moretti and Blander, 2014).
Inhibition of IL-1 may be achieved at different levels. Some substances target the IL-1 molecule directly (canakinumab, rilonacept, gevokizumab) while others are antagonists to the IL-1 receptor (anakinra) (Liu et al., 2014).
Glyburide is a sulfonylurea drug commonly used in the treatment of type 2 diabetes. It acts by inhibiting ATP-sensitive potassium channels in pancreatic β-cells. However, in addition to inhibiting IL-1β in response to ATP, glyburide can also inhibit production of IL-1β in response to multiple other NLRP3 stimuli (Ashcroft, 2005).
Colchicine has been used for the treatment of inflammatory disorders for centuries. Colchicine is effective in gout, but also in Behcet’s disease and FMF, where it is able to prevent amyloidosis (Gagliani et al., 2014).
Recent studies showed that an IFN-stimulated gene product, cholesterol 25-hydroxylase (Ch25h), antagonizes both IL1b transcription and NLRP3, NLRC4 and AIM2 inflammasome activation, suggesting Ch25h has a broad inhibitory activity of different inflammasomes. More importantly, the Ch25h substrate 25-hydroxycholesterol is able to inhibit NLRP3 inflammasome activation and IL-1β production (Guarda et al., 2011).
Recently, two additional small-molecule inhibitors that reduce NLRP3 activation have been reported. The ketone body β-hydroxybutyrate (BHB) was found to specifically inhibit a variety of stimuli triggering NLRP3 inflammasome activation. BHB inhibits the NLRP3 inflammasome by preventing potassium efflux and reducing ASC oligomerization and speck formation, although the direct target of BHB is still under exploration (Youm et al., 2015).
Another study found that the compound MCC950 is a highly selective inhibitor of the NLRP3 inflammasome. MCC950 blocked ATP, nigericin, monosodium urate and cytosolic LPS NLRP3-dependent inflammasome activation at nanomolar concentrations. In vivo, MCC950 has been shown to reduce IL-1β production (Coll et al., 2015)