Activation results in caspase-1
recruitment and proteolysis
This system has been studied for decades, yet relatively recently, a novel component was discovered - the inflammasome. On top of bein implicated in protecting against microbial pathogens it has also been shown to play a role in many autoinflammatory diseases, such as inflammatory bowel diseases and vitiligo. It is beginning to emerge as a central component in the regulation of our defences.
PAMPs, DAMPS and PRRs
Detected in many of our cells, the inflammasome is a multi-protein complex whose assembly is triggered by the detection of what are known as 'pathogen-associated molecular patterns' (PAMPs) - basically something our cells can detect which looks only like bacteria, virus, fungi or parasite. These PAMPS are sensed by cellular proteins known as 'pathogen recognition receptors' - (PRRs) e.g NALP3, on the inside or outside of the host cell; however, triggering can also result from the detection of chemical 'danger-associated molecular patterns' (DAMPS) compounds, including uric acid and asbestos. PRRs include: double stranded DNA, non-capped RNA and lipopolysacharride found in bacterial cell walls. Triggering of other PRRs results in the activation of many other immune responses, including autophagy, interfon secretion and cell signalling.
A pro-inflammatory signalling molecule
Formation of the inflammasome results in the activation of multiple pathways responsible for co-ordinating our immune response, yet interestingly, there are multiple forms of inflammasomes made up and triggered by different sets of proteins. This initial step of activation has been covered very well before, here. The activated inflammsome goes on to trigger key downstream members of our innate immune system through the recruitment of an important regulatory protease (it cuts up other proteins) - caspase 1, which converts inactive molecules to active, pro-inflammatory ones, such as interleukin-1 beta and interleukin-18. This 'inflammatory cascade' functions to initiate an effective local and systemic immune response through the control of the innate and adaptive immune system; for example, IL-beta is responsible for fever and the recruitment of immune cells to the site of infection, and IL-18 induces the development of key T cell responses.
Not all IL-1beta and IL-18?
Recent studies have shown that not all immune functions of the inflammasome are down purely to the effects of these two mediators; a number of other effectors are implicated in our complicated immune responses. Other responses activated by caspase-1 proteolysis include the better cell survival in the face of bacterial toxins; regulation of cellular metabolism limiting pathogen replication; induction of pyroptosis - a pro-inflammatory form of cell-death much like apoptosis and the secretion of high levels of multifuctional cytokines from the cell.
|Inflammatory 'pyroptosis' is looking to be an important mediator in the immune response|
All in all, the inflammasomes represent a fast and effective barrier to microbial infection in eukaryotic cells which, following detection of PAMPS and subsequent activation, results in a powerful innate immune response, stimulation of adaptive defences and significant contributions to over-all host defence using a variety of pathways.
Inflammasomes and viruses
Kanneganti, T. (2010). Central roles of NLRs and inflammasomes in viral infection Nature Reviews Immunology, 10 (10), 688-698 DOI: 10.1038/nri2851
Lamkanfi M (2011). Emerging inflammasome effector mechanisms. Nature reviews. Immunology, 11 (3), 213-20 PMID: 21350580
Martinon F, Burns K, & Tschopp J (2002). The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Molecular cell, 10 (2), 417-26 PMID: 12191486