Innate immune cells express several receptor systems that recognize microbes and induce rapid defenses as well as delayed cellular responses. Several scavenger and lectin-like receptors on neutrophils, macrophages, and dendritic cells help rapidly eliminate microbes through phagocytosis. G-protein-coupled receptors for C5a (which can be produced by activation of the complement system’s innate pathogen-recognition ability) and for the bacterial peptide fMLF synergize with phagocytic receptors in activating the NADPH oxidase in phagosomes to generate antimicrobial reactive oxygen intermediates. Toll-like receptors (TLRs) on the cell surface and in the membranes of endosomes detect microbes outside the cell and activate several host defense signaling pathways. The NFκB and IRF pathways downstream of these receptors induce pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, and antiviral cytokines including type I interferons. Other receptor families detect microbial infection in the cytosol. NOD proteins detect bacterial products within the cytosol and activate NFκB and the production of pro-inflammatory cytokines. The related NLR family of proteins detects signs of cellular stress or damage, as well as certain microbial components. NLRs signal through the inflammasome, which generates pro-inflammatory cytokines and induces pyroptosis, a form of cell death. RIG-I and MDA-5 detect viral infection by sensing the presence of viral RNAs and activate the MAVS pathway, while sensors of cytosolic DNA, such as cGAS, activate the STING pathway; both of these pathways induce type I interferons. The signaling pathways activated by all of these primary sensors of pathogens induce a variety of genes, including those for cytokines, chemokines, and co-stimulatory molecules that have essential roles in immediate defense and in directing the course of the adaptive immune response later in infection.
Induced innate responses to infection.
We will now examine the responses of innate immunity induced as an immediate consequence of pathogen recognition by the sensors described in the last section. We will focus on the major phagocytes—neutrophils, macrophages, and dendritic cells—and the cytokines they produce that induce and maintain inflammation. First, we will introduce the families of cytokines and chemokines that coordinate many cellular responses, such as the recruitment of neutrophils and other immune cells to sites of infection. We will discuss the various adhesion molecules that are induced on immune cells circulating in the blood and on endothelial cells of blood vessels to coordinate movement of cells out of the blood and into infected tissues. We will consider in some detail how macrophage-derived chemokines and cytokines promote the continued destruction of infecting microbes. This is achieved both by stimulating the production and recruitment of fresh phagocytes and by inducing another phase of the innate immune response—the acute-phase response—in which the liver produces proteins that act as opsonizing molecules, helping to augment the actions of complement. We will also look at the mechanism of action of antiviral interferons, the type I interferons, and finally examine the growing class of innate lymphoid cells, or ILCs, which include the NK cells long known to contribute to innate immune defense against viruses and other intracellular pathogens. ILCs exert a diverse array of effector function that contribute to a rapid innate immune response to infection. They respond to early cytokine signals provided by innate sensor cells, and amplify the response by producing various types of effector cytokines. If an infection is not cleared by the induced innate response, an adaptive response will ensue that uses many of the same effector mechanisms used by the innate immune system but targets them with much greater precision. The effector mechanisms described here therefore serve as a primer for the focus on adaptive immunity in the later parts of this book.
3-15 Cytokines and their receptors fall into distinct families of structurally related proteins.