Inflammasomes: Key Regulators of Inflammation

Inflammasomes are large, intracellular multiprotein complexes that play a crucial role in inflammation as an innate immune response to harmful stimuli. By sensing various pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), inflammasomes create inflammation thus facilitate the complete immune response to occur. Upon activation, inflammasomes license the maturation and secretion of proinflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18) to create and inflamed environment and guide the other immune cell to the site. These cytokines also induce a form of inflammatory cell death called pyroptosis in the area, to remove the infected cells.

Structure and Components of Inflammasomes
Inflammasomes are typically composed of three main components:
1) A sensor protein: This can be a member of the nucleotide-binding domain and leucine-rich repeat (NLR) family or the absent in melanoma 2 (AIM2)-like receptor (ALR) family. Examples include NLRP1, NLRP3, NLRC4, and AIM2.
2) An adaptor protein: Usually, the apoptosis-associated speck-like protein containing a CARD (ASC) serves as the adaptor, linking the sensor protein to the effector protein.
3) An effector protein: Most commonly the effector protein is caspase-1 , which is activated upon inflammasome assembly. However, other caspases (caspase-4, caspase-5 and caspase-12 in human)

Activation of Inflammasomes
Inflammasomes can be activated by a wide range of stimuli, including:
• Microbial pathogens and their components (e.g., bacterial toxins, viral DNA)
• Endogenous danger signals released from damaged or stressed cells (e.g., ATP, uric acid crystals, amyloid-β)
• Environmental irritants (e.g., silica, asbestos)

Upon activation, the sensor protein oligomerizes and recruits the adaptor protein ASC, which in turn recruits pro-caspase-1. This leads to the activation of caspase-1, which then cleaves and activates the proinflammatory cytokines IL-1β and IL-18.

Canonical and Non-canonical Functions of Inflammasomes
The canonical function of inflammasomes is to promote caspase-1-dependent maturation of IL-1β and IL-18, as well as to induce pyroptosis (due to their role in pyroptosis, they are also known as pyroptosomes), to fight infections or respond to cellular stress or damage. However, recent studies have revealed additional functions of inflammasomes that extend beyond their canonical roles:

• Regulation of eicosanoid storm
• Modulation of autophagy and metabolism
• Control of cellular proliferation and gene transcription
• Involvement in tumorigenesis

Role of Inflammasomes in Disease
Dysregulation of inflammasome activation has been implicated in various inflammatory and autoimmune diseases, including:
• Autoinflammatory diseases (e.g., Familial Mediterranean fever, cryopyrin-associated periodic syndromes)
• Metabolic disorders (e.g., type 2 diabetes, obesity)
• Neurodegenerative diseases (e.g., Multiple Sclerosis, Alzheimer's disease, Parkinson's disease)
• Cardiovascular diseases (e.g., atherosclerosis)

Therapeutic Targeting of Inflammasomes
Due to their central role in regulating the inflammation, inflammasomes have emerged as promising therapeutic targets. Several approaches are being explored to modulate inflammasome activity, such as:
• Small-molecule inhibitors targeting specific inflammasome components
• Biologics (e.g., monoclonal antibodies) blocking inflammasome-related cytokines
• Natural compounds with anti-inflammatory properties

However, further research is needed to overcome challenges in developing safe and effective inflammasome-targeted therapies.

Conclusion
Inflammasomes are crucial players in the innate immune response, linking the sensing of PAMPs and DAMPs to the activation of inflammatory pathways. The complexity of inflammasome biology, with its canonical and non-canonical functions, highlights the need for continued research to fully understand their role in health and disease. Targeting inflammasomes holds promise for the development of novel therapeutic strategies to combat various inflammatory disorders.

References:
Dai, Y., Zhou, J., & Shi, C. (2023). Inflammasome: structure, biological functions, and therapeutic targets. MedComm, 4(5), e391.
Bulté, D.; Rigamonti, C.; Romano, A.; Mortellaro, A. Inflammasomes: Mechanisms of Action and Involvement in Human Diseases. Cells 2023, 12, 1766.
Rathinam, V. A., & Fitzgerald, K. A. (2016). Inflammasome Complexes: Emerging Mechanisms and Effector Functions. Cell, 165(4), 792–800.