From the Guidelines
The inflammasome is a multiprotein complex that plays a crucial role in the innate immune response, recognizing danger signals and triggering inflammation through the activation of caspase-1 and the production of pro-inflammatory cytokines, as demonstrated in a study on the diverse roles of mitochondria in ischemic stroke 1.
Definition and Function
The inflammasome is composed of several proteins, with NLRP3 being one of the most well-studied components. It acts as a molecular sensor that detects signs of cellular damage, infection, or stress, and responds by initiating a cascade that leads to the production of pro-inflammatory cytokines, particularly interleukin-1β (IL-1β) and interleukin-18 (IL-18) 1.
Activation Mechanism
The activation of the inflammasome involves the recognition of danger signals, such as mitochondrial DNA (mtDNA) released into the cytosol, which can activate the NLRP3 inflammasome 1. This leads to the assembly of the inflammasome complex, activation of the enzyme caspase-1, and subsequent processing of the inactive pro-forms of IL-1β and IL-18 into their active forms.
Role in Disease
Excessive or inappropriate inflammasome activation contributes to various inflammatory diseases, including gout, type 2 diabetes, atherosclerosis, and neurodegenerative conditions 1. Understanding inflammasome function has led to the development of targeted therapies for inflammatory diseases, including IL-1 inhibitors that block the downstream effects of inflammasome activation.
Clinical Implications
In the context of ischemic stroke, the inflammasome plays a significant role in the inflammatory response, with NLRP3 protein levels increasing after ischemic stroke concurrently with elevated IL-1β and IL-18 expression and wide-ranging glial and neuronal death 1. The development of therapies targeting the inflammasome may offer innovative approaches to treating inflammatory diseases, including those related to ischemic stroke.
From the Research
Definition and Structure of Inflammasome
- Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response 2, 3, 4.
- Each inflammasome complex has three major components: a sensor molecule, an adapter protein, and a procaspase protein 2, 3, 4.
- The sensor protein detects pathogen-associated molecule patterns, damage-associated molecule patterns, and cellular stress, leading to the activation of the inflammasome 4.
Function and Activation of Inflammasome
- The activation of inflammasomes leads to the maturation of proinflammatory cytokines, such as IL-1β and IL-18, and pyroptotic cell death 2, 3, 4.
- Inflammasome formation typically occurs in response to infectious agents or cellular damage 2.
- The active inflammasome triggers caspase-1 activation, followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death 2, 3.
Role of Inflammasome in Human Diseases
- Aberrant inflammasome activation and activity contribute to the development of various diseases, including diabetes, cancer, cardiovascular, and neurodegenerative disorders 2, 3, 5.
- Inflammasome components have been identified in several human peripheral and brain tissues, and the inflammasome complex has been shown to be associated with several genetic and acquired inflammatory and neoplastic disorders 5.
- Modulation of the inflammasome has been proposed as a novel treatment for several inflammatory and neurodegenerative diseases, with ongoing clinical trials to test this theory 2, 5.