Seminars in immunopathology
-
Severe sepsis dominates the mortality of non-cardiac intensive care units. The ingenious Toll-like receptor (TLR) system can recognise many infectious organisms through relatively few receptors to trigger pro-inflammatory and anti-inflammatory cytokine release. Further complexity arises from positive and negative signalling feedback loops. ⋯ Therapies targeting these pathways are currently being evaluated. Alternatively, in clinical scenarios such as compensatory anti-inflammatory response syndrome, chronic viral sepsis or inadequate vaccine function, TLR signalling may be inadequate. TLR agonists may augment the innate response and are being investigated.
-
The innate immune system is a dynamic and complex network for recognizing and responding to cellular insult or tissue damage after infection or injury. The primary effector mechanism of innate immunity is the generation of acute and chronic inflammatory responses through regulation of the processing and activation of proinflammatory caspases, particularly caspase 1, and cytokines, most notably IL-1beta and IL-18. Inflammasomes, cytosolic multi-protein complexes that function as molecular scaffolds for caspase activation, have recently emerged as the pivotal mechanism by which host innate immune and inflammatory responses are regulated. In this review, we investigate the mechanisms by which inflammasomes are modulated, both by endogenous host systems and by microbial pathogens.
-
The innate immune system relies on a variety of pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) to sense microbial structures that are present in pathogens. Various levels of crosstalk between the TLR and NLR pathways have been described, most notably the description of a molecular scaffold complex, termed the inflammasome, which requires input from both pathways and leads to the activation of the proinflammatory cytokines interleukin (IL)-1beta and IL-18. In certain cases, the inflammatory process becomes dysregulated and chronic inflammatory diseases may develop. Understanding the interactions of the TLR and NLR pathways will provide further clues to the pathogeneses of these diseases and to the development of efficient therapies to combat them.