Fig. 5.2 ). Recognition of microbes by these receptors activates transcription factors that stimulate the production of several secreted and membrane proteins, including mediators of inflammation, anti-viral cytokines (interferons), and proteins that promote lymphocyte activation and the even more potent adaptive immune responses.
NOD-like receptors (NLRs) are cytosolic receptors named after the founding members NOD-1 and NOD-2. They recognize a wide variety of substances, including products of necrotic cells (e.g., uric acid and released ATP), ion disturbances (e.g., loss of K+), and some microbial products. How this family of sensors detects so many diverse signs of danger or damage is not known. Several of the NLRs signal via a cytosolic multiprotein complex called the inflammasome, which activates an enzyme (caspase-1) that cleaves a precursor form of the cytokine interleukin-1 (IL-1) to generate the biologically active form (
Fig. 5.3 ). As discussed in Chapter 3, IL-1 is a mediator of inflammation that recruits leukocytes and induces fever. Gain-offunction mutations in one of the NLRs result in periodic fever syndromes, called autoinflammatory syndromes,which respond very well to treatment with IL-1 antagonists. The NLR-inflammasome pathway also may play a role in a number of chronic disorders marked by inflammation. For example, recognition of urate crystals by a class of NLRs underlies the inflammation associated with gout. These receptors may detect and respond to lipids and cholesterol crystals that are deposited in abnormally large amounts in tissues; the resulting inflammation may contribute to obesity-associated type 2 diabetes and atherosclerosis, respectively.
C-type lectin receptors (CLRs) expressed on the plasma membrane of macrophages and DCs detect fungal glycans and elicit inflammatory reactions to fungi. Several cytosolic receptors detect the nucleic acids of viruses that replicate in the cytoplasm of infected cells, and stimulate the production of anti-viral cytokines. G protein–coupled receptors on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing N-formylmethionyl residues. Because all bacterial proteins and few mammalian proteins (only those synthesized within mitochondria) are initiated by N-formylmethionine, this receptor enables neutrophils to detect bacterial proteins and stimulates chemotactic responses. Mannose receptors recognize microbial sugars (which often contain terminal mannose residues, unlike mammalian glycoproteins) and induce phagocytosis of the microbes. In addition, two families of cytosolic receptors, one named after the founding member RIG-I and the other called cytosolic DNA sensors, recognize microbial RNA and DNA, respectively.
Signals from TLRs, other receptors