Inflammasomes are the central signaling hubs that activate the innate immune response, which is the body’s first line of defense against pathogens or other threats. The innate immune response is non-specific, activation is very rapid, and its effects are not lasting. Inflammasomes are molecular complexes comprised of the following:
Inflammasomes are molecular complexes comprised of the following:
Sensor molecules including NLRP1, , NLRP3, NLRC4, and AIM2 (NLRP3 best known)
Adaptor protein ASC
Each of the sensor molecules respond to different stimuli, and create a unique inflammasome defined by the sensor (i.e. NLRP3 Inflammasome). The adaptor protein, ASC, is associated with multiple sensor molecules and their associated 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
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:
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