Inflammasome
Inflammasomes are multiprotein complexes located in the cytosol. Typically, they consist of a sensor protein, an adaptor protein containing an caspase recruitment domain, and a pro-inflammatory caspase. In case of the NLRP3 inflammasome, presently the best characterized inflammasome, the respective proteins are NLRP3, ASC/PYCARD, and CASP1. The caspase promotes maturation of pro-inflammatory cytokines IL-1beta and IL-18 and Gasdermin D through proteolytic cleavage. Processing of IL-1beta and IL-18 and Gasdermin D drive pyroptosis, a highly inflammatory form of apoptosis. Subsequently to cleavage, the N-terminal part of Gasdermin D (GSDMD-N) localizes to the plasma membrane and forms pores through which IL-1beta and IL-18 are released. In addition, due to osmotic pressure the cells swells and ultimately bursts.
The formation of inflammasomes is triggered upon recognition of inflammatory stimuli by cytosolic pattern recognition receptors (PRRs). NOD-like receptors (NLRs) were the first class of these sensors to be discovered. More recently, AIM2-like receptors (ALRs) and RIG-I-like receptors (RLRs) have been added to this list. Assembly of different inflammasomes is in response to specific inflammatory ligands sensed by the respective receptors. These inflammatory ligands are molecular patterns that associated with pathogens (PAMPs) - such as bacteria, bacterial components (e.g. LPS , toxins, type III secretion systems components), and viruses - or with cellular damage (DAMPs) – such as nucleic acids, heat shock proteins, or markers for oxidative stress.
As part of the innate immune system, the primary role the inflammasome is likely the protection against invading pathogens. It is also involved in the initiation of the adaptive immune response through stimulation of the macrophages and regulation of Th17 cell differentiation. The NLRP3 inflammasome in particular has been implicated in metabolic disorders, allergic responses to environmental stimuli, and more recently in driving the cytokine storm in COVID-19.
References
- Schroder, K. & Tschopp, J. The Inflammasomes. Cell 140, 821–832 (2010).
- Davis, B. K., Wen, H. & Ting, J. P.-Y. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 29, 707–35 (2011).
- de Zoete, M. R., Palm, N. W., Zhu, S. & Flavell, R. A. Inflammasomes. Cold Spring Harb. Perspect. Biol. 6, a016287 (2014).
