In addition to TLRs, vertebrates use several other families of PRRs to detect pathogens. One is the large family of NOD-like receptors (NLRs). Like TLRs, NLRs have leucine-rich repeat motifs, but they are exclusively cytoplasmic and recognize a distinct set of bacterial molecules. Individuals who are homozygous for a particular mutant allele of the NLR gene NOD2 have a greatly increased risk of developing Crohn’s disease, a chronic inflammatory disease of the small intestine, possibly triggered by a bacterial infection. Another class of PRRs consists of RIG‑like receptors (RLRs), which are members of the RNA helicase family of proteins. They are also exclusively cytoplasmic and detect viral pathogens. A fourth class of PRRs consists of C‑type lectin receptors (CLRs), which are trans-membrane cell-surface proteins that recognize carbohydrates (which is why they are called lectins) on various microbes. Table 24–1 summarizes some PRRs and their ligands and locations in cells. Collectively, these and other PRRs act as an alarm system to alert the innate and adaptive immune systems that an infection is brewing (Movie 24.1).
When a cell-surface or intracellular PRR binds a PAMP, it stimulates the cell to secrete a variety of cytokines and other extracellular signal molecules. Some of these inhibit viral replication, but most induce a local inflammatory response that helps eliminate the pathogen, as we now discuss.
Activated prrs Trigger an Inflammatory response at Sites of Infection
When a pathogen invades a tissue, it activates PRRs on or in various cells of the innate immune system, resulting in an inflammatory response at the site of infection. The inflammatory response depends on changes in local blood vessels and is characterized clinically by local pain, redness, heat, and swelling. The blood vessels dilate and become permeable to fluid and proteins, leading to local swelling and an accumulation of blood proteins that aid in defense. At the same time, the endothelial cells lining the local blood vessels are stimulated to express cell adhesion proteins, which promote the attachment and escape of white blood cells or leukocytes (see Figure 19–29B), adding to the local swelling; initially neutrophils escape, followed later by lymphocytes and monocytes (the blood-borne precursors of macrophages).
The activation of PRRs results in the production of a large variety of extracellular signal molecules that mediate the inflammatory response at the site of an infection. These include both lipid signal molecules, such as prostaglandins, and protein (or peptide) signal molecules called cytokines. Some of the most important pro-inflammatory cytokines are tumor necrosis factor‑α (TNFα), interferon‑γ (IFNγ), a variety of chemokines (which recruit leukocytes), and various interleukins (ILs) that we discuss later, including IL1, IL6, IL12, and IL17. In addition, a secreted PRR (mannose-binding lectin) activates the complement system when the PRR binds to a pathogen; fragments of complement proteins released during complement activation stimulate an inflammatory response (discussed shortly; see Figure 24–7).