Innate immune cells act as a surveillance system, detecting and responding to pathogens and endogenous danger signals. The complex patterns of signals that are received are detected by a variety of pattern recognition receptors (PRRs). In the main article [attached] authors find that innate immune responses to microbial products do not occur in a vacuum; rather, there is a complex array of danger signals in surrounding damaged tissue that can determine an immune cell type–specific response to pathogens. Authors describe a host-derived lipid that binds to a PRR to induce a hyperactive innate immune response that enhances long-lived protective immunity against invading microbes.
Caspase-11 is a unique cytosolic PRR that binds to, and is activated by, lipopolysaccharide (LPS), a microbial-derived lipid found in the outer leaflet of Gram-negative bacteria. In macrophages, one of the innate immune cell types, LPS binds to and activates caspase-11, inducing caspase-11– and caspase-1–dependent pyroptosis, or inflammatory cell death. Activation of caspase-11 by LPS also induces the cleavage of gasdermin-D (GSDMD), a protein whose physiological role is still unknown, and may act as an executioner protein during pyroptosis.
Pyroptosis is associated with the release of proinflammatory cytokines interleukins IL1a/b, IL18, and high-mobility group box 1 (HMGB1) from multiple cell types, which correlates with protection and clearance of bacterial pathogens and contributes to exacerbation of sepsis. Although caspase-11 plays an important role in responding to microbial lipids, it was unknown whether it can bind and respond to additional ligands.
Authors describe a newly discovered host-derived caspase-11 ligand: oxidized phospholipids, a group of lipids released from dying cells in damaged tissue. The combination of microbial products and the oxidized phospholipid oxPAPC triggers release of the potent proinflammatory cytokine IL-1b from dendritic cells without inducing pyroptosis. Authors describe this enhanced dendritic cell activation state as “hyperactive”. Interestingly, this hyperactive state was not found in macrophages, which suggests that oxPAPC inhibition of caspase-11–dependent cell death is cell type–specific. The specificity of this regulatory effect will likely prove to be important in the complex innate immune response and subsequent adaptive immune responses during microbial infection in a whole organism.
Science 3 June 2016; 352: 1232–1236 [main article] + pp 1173–1174 [Insights]