Homeostasis-altering molecular processes as mechanisms of inflammasome activation

The innate immune system uses a distinct set of germline-encoded pattern recognition receptors (PRRs) to initiate downstream inflammatory cascades. This recognition system is in stark contrast to the adaptive immune system, which relies on highly variable, randomly generated antigen receptors. A key limitation of the innate immune system's reliance on fixed PRRs is its inflexibility in responding to rapidly evolving pathogens. Recent advances in our understanding of inflammasome activation suggest that the innate immune system also has sophisticated mechanisms for responding to pathogens for which there is no fixed PRR. This includes the recognition of debris from dying cells, known as danger-associated molecular patterns (DAMPs), which can directly activate PRRs in a similar manner to pathogen-associated molecular patterns (PAMPs). Distinct from this, emerging data for the inflammasome components NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and pyrin suggest that they do not directly detect molecular patterns, but instead act as signal integrators that are capable of detecting perturbations in cytoplasmic homeostasis, for example, as initiated by infection. Monitoring these perturbations, which we term 'homeostasis-altering molecular processes' (HAMPs), provides potent flexibility in the capacity of the innate immune system to detect evolutionarily novel infections; however, HAMP sensing may also underlie the sterile inflammation that drives chronic inflammatory diseases.