Acute inflammation is the central feature of innate immunity. The first step in the inflammatory process is the early detection of either invading organisms or damaged tissues. Most invaders are recognized by pattern-recognition receptors that bind and recognize conserved molecules expressed on microbial surfaces. These pathogen-associated molecular patterns (PAMPs) are one type of initiating trigger. The second type of trigger are molecules released from broken or damaged cells. These are called damage-associated molecular patterns (DAMPs). There are many different pattern-recognition receptors, but the most important are the toll-like receptors (TLRs). TLRs are a family of at least 10 different receptors found on the surface or in the cytoplasm of cells such as macrophages, intestinal epithelial cells, and mast cells. The TLRs bind to PAMPs commonly expressed by extracellular bacteria such as lipopolysaccharides, flagellin, and lipoproteins. The cytoplasmic TLRs, in contrast, bind the nucleic acids of intracellular viruses. Once they bind these ligands, the TLRs trigger the production of inflammatory cytokines such as interleukin 1 (IL-1) or tumor necrosis factor alpha (TNF-alpha).
IL-1 and the other cytokines produced in response to TLR stimulation then trigger acute inflammation. They initiate the adherence of circulating leukocytes to blood vessel walls close to sites of invasion. These leukocytes, especially neutrophils, then leave the blood vessels and migrate to invasion sites, attracted by microbial products, small proteins called chemokines, and molecules from damaged cells. Once they arrive at the invasion site, the neutrophils bind invading bacteria, ingest them by phagocytosis, and kill them. This is largely mediated by a metabolic pathway called the respiratory burst that generates potent oxidants such as hydrogen peroxide and hypochloride ions. Neutrophils, however, have minimal energy reserves and can only undertake few phagocytic events before they are depleted.
Even when the inflammatory response is successful in killing invading microbes , the body must still remove cell debris and dying cells and repair the damage. This is the task of macrophages. Tissue macrophages originate from blood monocytes. They, like neutrophils, are attracted to sites of microbial invasion and tissue damage by chemokines, DAMPs, and PAMPs, where they finish off any surviving invaders. They also ingest and destroy any remaining neutrophils, thus ensuring that the neutrophil oxidants are removed without toxic spills occurring in the tissues. Finally, another population of macrophages begins the process of tissue repair. Macrophages that complete the destructive process are optimized for microbial destruction and are called M1 cells. Macrophages optimized for tissue repair and removal of damaged tissues are called M2 cells.
Many of the molecules produced as a result of inflammation and tissue damage, such as IL-1 and TNF, can leak into the bloodstream, where they circulate. They can enter the brain and trigger sickness behavior; for example, they cause a fever, suppress appetite, and produce sleepiness and depression. They also mobilize energy reserves from fat and muscle. This sickness behavior is believed to enhance the defense of the body by redirecting energy toward fighting off invaders.
Circulating cytokines from inflammatory sites also act on liver cells, causing the cells to secrete a mixture of “acute-phase proteins,” so-called because their blood levels climb steeply when acute inflammation develops. Different mammals produce different acute-phase proteins, including serum amyloid A, C-reactive protein, and many different iron-binding proteins.
The Complement System in Animals
Acute inflammation is central to innate immunity, but the body possesses other innate defenses. Tissues contain many antimicrobial peptides. These include detergent-like proteins such as the defensins or cathelicidins that can lyse bacterial cell walls; enzymes such as lysozyme that kill many gram-positive bacteria; and iron-binding proteins such as hepcidin or haptoglobin that prevent bacterial growth by depriving them of essential iron. The most important of these innate defenses is the complement system, which consists of a group of approximately 30 proteins that act collectively to kill invading microbes. The primary function of the complement system is to bind two proteins called C3 and C4 covalently, and hence irreversibly, to microbial surfaces. Once bound, these complement components may either kill microbes by rupturing them using another protein called C9 or simply coat them so that they are rapidly and effectively phagocytized by leukocytes.
The complement system can be activated in three ways. One way, called the alternative pathway, is triggered by the presence of bacterial surfaces that can bind the complement protein C3. Once bound, C3 acts as an enzyme to activate and bind more C3. These C3-coated bacteria are rapidly and effectively phagocytized and destroyed. Alternatively, surface-bound C3 can activate additional complement components that eventually cause a protein called C9 to insert itself within bacterial cell walls, where it causes bacterial rupture. A second complement-activating pathway is triggered when bacterial surface carbohydrates bind to a mannose-binding protein in serum. This binding activates an enzyme pathway that leads, in turn, to activation of C3 or C9. The third, or classic, pathway of complement activation is triggered when antibodies bind to microbial surfaces. It is thus triggered by adaptive immune responses. Like the mannose pathway, this eventually leads to activation of C3 and C9. Because of its potential to cause severe tissue damage, the complement system is carefully controlled through multiple complex regulatory pathways.
Cells of Innate Immunity in Animals
The key to an effective innate immune response is prompt recognition of invasion and a rapid cellular response. Several cell types function as sentinel cells. The most important are macrophages, dendritic cells, mast cells, and innate lymphoid cells. Macrophages, dendritic cells, and mast cells express pattern recognition receptors and can sense the presence of PAMPs and DAMPs. When these receptors are engaged, they signal through a molecule called NF-κB to turn on the production of cytokines such as IL-1, interferon (IFN)-alpha, and TNF-alpha. They also release vasoactive and pain molecules such as histamine, leukotrienes, prostaglandin, and specialized peptides that initiate the vascular events in inflammation.
The purpose of inflammation is to ensure that leukocytes converge in large numbers to sites of microbial invasion. This involves attracting these cells from the bloodstream where they circulate and inducing them to migrate through the tissues to the invasion sites. Three major leukocyte populations can kill invaders. Neutrophils are especially effective at killing invading bacteria. They engulf the invaders, activate the respiratory burst, and generate lethal oxidizing molecules such as hydrogen peroxide and hypochloride ions that kill most ingested bacteria. Eosinophils are specialized killers of invading parasites. They contain enzymes optimized to kill migrating helminth larvae. The third major killing cell population are M1 macrophages. These cells migrate into areas of microbial invasion more slowly than granulocytes. However, they are capable of sustained and effective phagocytosis. They contain the highly lethal antimicrobial factor nitric oxide and thus can kill organisms resistant to neutrophil killing.
When inflammation activates macrophages, they secrete a cytokine called IL-23. This, in turn, acts on a subset of T cells (called Th17 cells), causing them to secrete IL-17. IL-17 recruits neutrophilic granulocytes to sites of inflammation, infection, and tissue damage.
Although many leukocytes are optimized to kill invading bacteria, viruses also present a potent threat. Animals possess at least four populations of innate lymphoid cells (ILC) that participate in innate immunity. Group one innate lymphoid cells (ILC1) are found in large numbers in the intestinal wall. They secrete macrophage-activating cytokines and play a key role in antiviral immunity. Group two innate lymphoid cells are scattered through the body and secrete cytokines that are important in antiparasite immunity. Group three innate lymphoid cells act like Th17 cells and promote inflammation by releasing IL-17. Natural killer (NK) cells are a population of innate lymphoid cells optimized to kill virus-infected cells. NK cells can kill virus-infected or other “abnormal” cells that fail to express major histocompatibility complex (MHC) class I molecules. MHC class I molecules are present normally on all nucleated cells of the body. They bind to NK cell receptors and switch off their killing abilities. Some viruses down-regulate expression of MHC class I molecules on the surface of cells they infect. In the absence of this MHC class I binding signal, the NK cells bind to the virus-infected target cells, inject them with proteins that induce cell death and thus eliminate the virus-infected cells.
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