When activated by PAMPs, most cell-surface and intracellular PRRs stimulate the production of multiple pro-inflammatory cytokines by activating intracellular signaling pathways that switch on transcription regulators, including NFκB, to induce the transcription of the relevant cytokine genes (see Figure 15–62). Some PRRs, however, can also stimulate pro-inflammatory cytokine production by a different mechanism: when activated, several cytoplasmic NLRs assemble with adaptor proteins and specific protease precursors of the caspase family (discussed in Chapter 18) to form inflammasomes, in which pro-inflammatory cytokines such as IL1 are cleaved from their inactive precursor proteins by activated caspases. These cytokines are then released from the cell by a poorly understood, unconventional secretion pathway. Inflammasomes closely resemble apoptosomes in their assembly and structure, but, in apoptosomes, procaspases are activated to initiate a proteolytic caspase cascade that leads to apoptosis (see Figure 18–7).
NLR-dependent inflammasome assembly can also be triggered in the absence of infection if cells are damaged or stressed. Such cells produce “danger signals,” such as altered or misplaced self molecules, which can activate the relevant NLRs: the arthritis caused by uric acid crystals formed in the joints of individuals with gout, who have abnormally high uric acid levels in their blood, is a painful example.
phagocytic cells Seek, engulf, and Destroy pathogens
In all animals, the recognition of a microbial invader is usually quickly followed by its engulfment by a phagocytic cell. Macrophages are long-lived phagocytes that reside in most vertebrate tissues; they are among the first cells to encounter invading microbes, whose PAMPs activate the macrophages to secrete pro-inflammatory signal molecules. Neutrophils are short-lived phagocytes that are abundant in blood but are not present in healthy tissues; they are rapidly recruited to sites of infection by various attractive molecules, including formylmethionine-containing peptides (which are released by microbes but are not made by mammalian cells), chemokines secreted by activated macrophages, and peptide fragments produced from cleaved, activated complement proteins. The recruited neutrophils contribute their own pro-inflammatory cytokines.
In addition to their PRRs, macrophages and neutrophils display a variety of cell-surface receptors that recognize fragments of complement proteins or antibodies bound to the surface of a pathogen. The binding of such a pathogen to these receptors leads to its phagocytosis (Figure 24–5) and an attack on the ingested pathogen once inside a phagolysosome. The phagocytes possess an impressive armory of weapons to kill the invader, including enzymes such as lysozyme and acid hydrolases that can degrade the pathogen’s cell wall. The cells assemble NADPH oxidase complexes on the phagolysosomal membrane, where the complexes catalyze the production of highly toxic oxygen-derived compounds, including superoxide (O2–), hydrogen peroxide, and hydroxyl radicals. A transient increase in oxygen consumption by the phagocytic cells, called the respiratory burst, accompanies the production of these toxic compounds. Whereas macrophages generally survive this killing frenzy and live to kill again, neutrophils do not. Dead and dying neutrophils are a major component of the pus that forms in acute bacterially infected wounds; their half-life in the human bloodstream is only a few hours.