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:

  • A sensor molecule, which may include NLRP1, NLRP2, NLRP3, NLRC4, AIM2, and Pyrin (NLRP3 best known)
  • Adaptor ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain or CARD)
  • Pro-caspase 1

In the presence of harmful pathogens or internal stressors, the protein components assemble into an inflammasome.  Each of the sensor molecules respond to different stimuli, and create a unique inflammasome, which is named by the sensor molecule (i.e. NLRP3 Inflammasome).

The adaptor ASC, is associated with multiple inflammasomes as depicted below. Its role is to recruit procaspase 1 into the inflammasome. ASC is pivotal for activation and perpetuation of inflammation.

Inflammasomes


How do inflammasomes activate the innate immune response1-3?

Inflammasomes activate the innate inflammatory response, as follows:

  • In response to pathogens or other immune triggers, an intracellular sensor molecule (i.e. NLRP3) recruits ASC, which recruits pro-caspase-1 to form the NLRP3 inflammasome
  • The NLRP3 inflammasome is the organizing center that recruits additional ASC and pro-caspase-1 to form a large filamentous signaling platform, known as an ASC Speck
  • ASC Specks provide a scaffold for optimal pro-caspase-1 recruitment, and trigger conversion of pro-caspase 1 to active caspase 1, which converts pro-IL-1β to the active cytokine IL-1β, which triggers the inflammation process
  • ASC Specks are released outside the cell to create a signaling platform that induces a massive extracellular inflammatory response
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, 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 1 diabetes, rheumatoid arthritis, multiple sclerosis, and Crohn’s disease, which affect 5-7% o of the population in Western Societies.

Multiple inflammasomes are linked to each of numerous 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