Foreign bodies (splinters, dirt, sutures) may elicit inflammation by themselves or because they cause traumatic tissue injury or carry microbes. Even some endogenous substances stimulate potentially harmful inflammation if large amounts are deposited in tissues; such substances include urate crystals (in the disease gout), and cholesterol crystals (in atherosclerosis).
Immune reactions (also called hypersensitivity) are reactions in which the normally protective immune system damages the individual’s own tissues. The injurious immune responses may be directed against self antigens, causing autoimmune diseases, or may be inappropriate reactions against environmental substances, as in allergies, or against microbes. Inflammation is a major cause of tissue injury in these diseases (Chapter 5). Because the stimuli for the inflammatory responses in autoimmune and allergic diseases (self and environmental antigens) cannot be eliminated, these reactions tend to be persistent and difficult to cure, are often associated with chronic inflammation, and are important causes of morbidity and mortality.
The first step in inflammatory responses is the recognition of microbes and necrotic cells by cellular receptors and circulating proteins. The cells and receptors that recognize invaders evolved as adaptations of multicellular organisms to the presence of microbes in the environment, and the responses they trigger are critical for survival.
• Cellular receptors for microbes. Phagocytes, dendritic cells (cells in epithelia and all tissues whose function is to capture microbes), and many other cells express receptors that detect the presence of infectious pathogens. The best defined of these receptors belong to the family of Toll-like receptors (TLRs), which are named for the founding member, Toll, a gene that was discovered in Drosophila (Chapter 5). TLRs are located in plasma membranes and endosomes, so they are able to detect extracellular and ingested microbes. Other microbial sensors are present in the cytoplasm of cells. TLRs recognize motifs common to many microbes, often called pathogen-associated molecular patterns (PAMPs). Recognition of microbes by these receptors stimulates the production and expression of a number of secreted and membrane proteins. These proteins include cytokines that induce inflammation, anti-viral cytokines (interferons), and cytokines and membrane proteins that promote lymphocyte activation and even more potent immune responses. We will return to TLRs in more detail in Chapter 5, when we discuss innate immunity, the early defense against infections.
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Sensors of cell damage. All cells have cytosolic receptors that recognize molecules that are liberated or altered as a consequence of cell damage, and are hence appropriately called damage-associated molecular patterns (DAMPs). These molecules include uric acid (a product of DNA breakdown), ATP (released from damaged mitochondria), reduced intracellular K+ concentrations (reflecting loss of ions because of plasma membrane injury), DNA (when it is released into the cytoplasm and not sequestered in nuclei, as it should be normally), and many others. The receptors activate a multiprotein cytosolic complex called the inflammasome, which induces the production of the cytokine interleukin-1 (IL-1). IL-1 recruits leukocytes and thus induces inflammation (discussed later). Gain-of-function mutations in the cytosolic receptors are the cause of rare diseases known as autoinflammatory syndromes that are characterized by spontaneous inflammation; IL-1 antagonists are effective treatments for these disorders. The inflammasome also has been implicated in inflammatory reactions to urate crystals (the cause of gout), cholesterol crystals (in atherosclerosis), lipids (in metabolic syndrome and obesity-associated diabetes), and amyloid deposits in the brain (in Alzheimer disease). These disorders are discussed in relevant chapters.