Inflammasomes

What are inflammasomes1?

Inflammasomes are important signaling complexes that play a critical role in innate immunity, the body’s first line of defense against foreign infectious organisms and cell damage. They also potentiate the adaptive immune response. Inflammasomes are molecular complexes comprised of three basic proteins:

  1. A sensor molecule, which may include NLRP1, NLRP2, NLRP3, NLRP6, NLRP7, NLRC4, NLRC5, NAIP2, NAIP5, NAIP6, AIM2, and Pyrin (NLRP3 best known)
    • Each of the sensor molecules responds to different stimuli, and creates a unique inflammasome, named by the sensor molecule
  1. Adaptor ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain or CARD)
    • Adaptor ASC is associated with each of the 12 above mentioned sensor molecules and their associated inflammasomes
  1. Pro-caspase 1

In the presence of harmful pathogens or internal stressors, the three protein components assemble into an inflammasome, of which six are depicted below.

Inflammasomes


How do inflammasomes activate the innate immune response1-3?

Inflammasomes activate the innate inflammatory response, as follows:

Upon sensing threat, the relevant receptor undergoes oligomerization and conformational change into a pinwheel-like shape in order to make their pyrin domains available for binding to adaptor ASC. The activated inflammasome serves as a docking platform for additional ASC molecules, which polymerize to form a large filamentous signaling platform known as an ASC Speck. ASC Specks provide a scaffold for pro-caspase-1, which is cleaved into active caspase-1, which in turn, triggers activation of the pro-forms of cytokines IL-1β and pro-IL-18 into their active forms, initiating the inflammatory process. Active caspase-1 also cleaves Gasdermin D into its active form, which triggers cell death, known as pyroptosis, releasing active cytokines and ASC Specks into the extracellular space. Extracellular cytokines and ASC Specks continue to produce active cytokines, heightening and perpetuating the inflammatory response in neighboring cells and tissues.

Inflammasome Formation
Inflammasome Formation
ASC Speck
ASC Speck

What is the role of inflammasomes in the adaptive inflammatory response3?

The adaptive inflammatory response is activated when the innate immune response is inadequate. It responds to a specific immune trigger (antigen) and has memory for that specific antigen for efficient response to future encounters with the antigen.

Through activation of cytokines, inflammasomes amplify T and B cell responses. IL-1β can act on lymphocytes in several ways including upregulating IL-2 receptor expression, prolonging survival of T cells, enhancing antibody production by B cells, and increasing B cell proliferation. IL-1β and IL-18 play a critical role in driving the differentiation and amplification of Th17 and Th1 cells, respectively.

What is the role of inflammasomes in disease3-6?

Although the immune system is critical for health, when dysregulated,excessive and/or chronic activation of the immune system can occur, including development of inflammation against the body’s own cells, resulting in immune-related inflammatory disorders. There are over 80 inflammatory disorders, including type obesity, atherosclerosis, acute respiratory distress syndrome, multiple sclerosis, Parkinson’s and Alzheimer’s diseases, which affect 5-7% of the population in Western Societies.

Activation of more than one type of inflammasome has linked to many inflammatory disorders, as seen in the table below:

Inflammasomes Table

References

  1. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21(7):677-87
  2. Franklin BS, Bossaller L, De Nardo D, et al. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol. 2014;15(8):727-37
  3. Shaw PJ, McDermott MF, Kanneganti TD. Inflammasomes and autoimmunity. Trends Mol Med. 2010;17(2):57-64
  4. El-Gabalawy, H., Guenther, Lyn C., and Bernstein, Charles, N. (2010). Epidemiology of Immune-Mediated Inflammatory Diseases: Incidence, Prevalence, Natural History, and Comorbidities. The Journal of Rheumatology Supplement. May 2010, 85, 2-10
  5. Arakelyan A, Nersisyan L, Poghosyan D, et al. Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles. PLoS One. 2017;12(11)
  6. Kuek A, Hazleman BL, Ostör AJ. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad Med J. 2007;83(978):251-60