Introduction:
Inflammation is the defense mechanism of the body to protect it from various infections and foreign substances. It is a biological response of the body to remove foreign substances. The immune system activates inflammatory cells whenever the body encounters a foreign body, such as a virus, bacteria, or toxins, or suffers an injury. The cytokines are the first responders, stimulating the inflammatory response. Cytokines are the small proteins that control the growth and activity of other immune system cells and blood cells.
The immune system cells are the major players in mediating inflammatory responses against any stimuli. These cells act as signaling receptors that help detect foreign substances, and inflammasome complexes get formed when persistent inflammation occurs. This help activates certain enzymes and produces pro-inflammatory cytokines and pyroptosis induction (inflammatory cell death caused by microbial infection).
What Are Inflammasomes?
Inflammasomes are defined as high-molecular-weight cytoplasmic multiprotein complexes which are responsible for the activation of the inflammatory response to any external stimuli. The inflammasomes help regulate the activation of caspase-1 (a family of protease enzymes playing essential roles in programmed cell death) and induce inflammation in response to infectious microbes and molecules derived from host proteins. Moreover, it has been implicated in a host of inflammatory disorders. The activation and assembling of inflammasomes promote the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18, leading to pyroptosis (inflammatory cell death caused by microbial infection).
What Is the History of Inflammasomes?
Tschopp and coworkers first discovered the inflammasomes in 2002 in diseases such as type 2 diabetes and gout. Their study found that various signals can stimulate the response from an inflammasome, such as viral DNA, asbestos, muramyl dipeptide (MDP), and silica. They also found a connection between metabolic syndrome and NLRP3, a subtype of the inflammasome. Tschopp and his coworker's work helps evaluate and treat various major diseases.
Later in 2002, Martinon and his coworkers found that a subset of NLRs (NOD-like receptors) (NOD-nucleotide-binding oligomerization) named NLRP1 assembled into a common structure, collectively activating the caspase-1 cascade, thereby producing pro-inflammatory cytokines such as IL-1β and IL-18. This NLRP1 complex was considered the first inflammasome found, which led to more interest from the scientists, and later on, several other inflammasomes were discovered, such as NLR subtypes - NLRP3 and NLRC4.
The nucleotide-binding oligomerization- (NOD-) like receptors (NLRs) are a type of pattern recognition receptor (PRR) and are located within the cytoplasm of a cell and help in recognizing the pathogen/damage-associated molecular patterns (PAMPs/DAMPs). The NLRs include Toll-like receptors (TLRs), C-type lectins (CTLs), and galectins, which help mediate the innate immune response to identify harmful microbes or other pathogens.
What Is the Structure of Inflammasomes?
The inflammasome complexes are formed by three important molecular structures: a sensor molecule, an adaptor protein, and an effector, for example, caspase-1. The sensor molecules identified to participate in the assembly process include the following:
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Nucleotide-binding oligomerization domain (NOD).
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Leucine-rich repeat (LLR).
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NOD-like receptors (NLRs) family.
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Absent in melanoma 2- (AIM2-) like receptors (ALRs) family.
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Interferon-inducible protein 16 (IFI-16).
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Retinoic acid-inducible gene I (RIG-I).
Once these sensor molecules are activated, they help promote apoptosis-associated speck-like protein containing a caspase activation (ASC) and recruitment domain (CARD), which helps activate specific caspases.
The protein components of NLR inflammasomes are present in their structure death domains (DD - protein-protein interaction structures found in proteins that regulate various signal transduction pathways), which are represented by pyrin domains (PYD), NLRP, or CARD domains. The NLR family - NLRP1, 3, 4, 6, 7, and NLRC12 are capable of inflammasome complex formation after receptor activation. There are four known NLRP inflammasomes, including NLRP1, NLRP3, NLRP4, and AIM2 inflammasomes. Among these, NLRP3 inflammasomes play a vital role in shaping immune responses and regulating intestinal homeostasis in various inflammatory diseases.
What Are the Components of Inflammasome Complexes?
The inflammasome complexes consist of three major molecules, including:
1. Pattern Recognition Receptors (PRRs) - The PRR receptors comprise Toll-like receptors (TLRs) and C-type lectin (CTL), which are membrane-bound receptors and cytoplasmic receptors such as NLRs, RIG-I-like receptors (RLRs), and ALRs.
2. Adaptor protein (ASC - apoptosis-associated speck-like protein containing a CARD) - It is based on two protein-protein interaction domains - an N-terminal PYD domain and a C-terminal CARD domain. The primary function of the ASC protein is to connect with the complex assembly involved in inflammatory processes and automated cell death.
3. Caspase Family - The caspase family can be divided into multiple domains depending upon their involvement in inflammation or apoptosis, which include
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Inflammatory caspases (caspase-1, caspase-4, and caspase-5).
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Caspases involved in apoptosis initiation (caspase-2, caspase-8, caspase-9, and caspase-10).
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Caspases required for apoptosis advancement (caspase-3, caspase-6, and caspase-7).
What Is the Mechanism of Activation of Inflammasomes?
The mechanism of activation of inflammasomes is listed below:
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Inflammasomes are the protein complexes that assemble in the cytoplasm of body cells after sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Specific sensors such as PRRs pattern recognition receptors or TLRs Toll-like receptors can recognize this distinct stimulus depicted by PAMPs or DAMPs.
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After sensing, the PAMPS and DAMPs receptor molecules get assembled and will further activate the caspase-1.
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The activated receptor molecules engage with the adaptor protein ASC, which engages the procaspase-1 and determines its activation through oligomerization which is a process that allows proteins to form large structures and provides stability to the complex.
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After that, the active caspase-1 helps the cleavage (breakdown) and maturation of IL-1β and IL-18, which promotes the secretion of other inflammatory factors and causes pyroptosis (inflammatory cell death caused by microbial infection).
There are two other noncanonical pathways of inflammasome activation, including other caspases instead of caspase-1.
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The first one evaluates the capacity of lipopolysaccharides (LPS) to activate caspase-4 and caspase-5 through toll-like receptor 4 (TLR4). This will further simulate the processing of gasdermin D (GSDMD - a protein encoded by the GSDMD gene on chromosome 8) to activate the inflammasome complex. After the activation of the inflammasome, IL-1β and IL-18 maturation will occur in a caspase-1-dependent manner and will facilitate the process of pyroptosis.
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The second method is represented by IL-1β and IL-18 maturation through the activation of caspase-8, which is activated through microbes' detection by CTL (C-type lectin) receptors.
What Is the Link Between Inflammasomes and Auto-Inflammatory Diseases?
Inflammasomes have been linked with various autoinflammatory and autoimmune diseases, including neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease and metabolic disorders like atherosclerosis, type-2 diabetes, and obesity.
Below are some of the associated auto-inflammatory diseases and their pathologic activation of inflammasomes or NLRs.
Hereditary Periodic Fevers:
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Cryopyrinopathies (MWS, FCAS, NOMID) - Mutation in CIAS1 or NLRP3. Overactive variants of NLRP3 and overexpression of NLRP3 lead to facilitated inflammasome activation.
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Familial Mediterranean Fever (FMF) - Mutations in MEFV or pyrin. Possible promotion of ASC assembly.
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NLRP12 Familial Fever - Truncation mutations in NLRP12. Hereditary periodic fevers associated with arthralgia (joint stiffness) and urticaria (raised, itchy skin rash).
Genetic Diseases:
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Vitiligo - Mutations in NLRP1.
Crystal-induced Diseases:
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Gout - A complex form of arthritis. MSU crystals. Activation of the NLRP3 inflammasome.
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Pseudogout - A form of arthritis characterized by sudden, painful swelling in one or more of the joints. Calcium pyrophosphate dehydrates. Activation of the NLRP3 inflammasome.
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Asbestosis - A lung disease caused by breathing in particles of asbestos. Asbestos. Activation of the NLRP3 inflammasome.
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Silicosis - A long-term lung disease caused by inhaling large amounts of crystalline silica dust. Silica. Activation of the NLRP3 inflammasome.
Other -
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Alzheimer's Disease - β-Amyloid. Activation of the NLRP3 inflammasome.
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Contact Hypersensitivity - Trinitrochlorobenzene, sodium dodecyl sulfate. Activation of the NLRP3 inflammasome.
Conclusion:
The inflammasomes are vital cellular complexes that help detect pathogens and endogenous danger signals. In addition, they help in immunity as they promote the production of interleukins IL-1β and IL-18. Therefore, the effectiveness of any drug that can alter the inflammasome function can potentially improve the symptoms of various autoinflammatory diseases like crystal-induced inflammation. Therefore inflammasome activity is considered critical to check the host response to microbial pathogens and the response of the body's immunity to medicine.
Hence, inflammasome activation cannot be considered harmful as it has multiple beneficial factors. As the research is still going on these factors, there is a high chance that new therapies will be developed in the coming future to tackle various inflammatory diseases.
