The importance of some of the individual molecules involved in the generation of innate and inflammatory responses is dramatically demonstrated by the impact on human health of genetic defects and polymorphisms (genetic variants) that alter the expression or function of these molecules (see Clinical Focus Box 4-3). As illustrated by these conditions, and by the many known roles (cited throughout this chapter) of innate and inflammatory mechanisms in protecting us against pathogens, these responses are essential to keeping us healthy. Some disorders show that innate and inflammatory responses can also be harmful, in that overproduction of various normally beneficial mediators and uncontrolled local or systemic responses can cause illness and even death. Therefore it is important that the occurrence and extent of innate and inflammatory responses be carefully regulated to optimize the beneficial responses and minimize the harmful responses.
To be optimally effective in keeping us healthy, innate and inflammatory responses should use their destructive mechanisms to eliminate pathogens and other harmful substances quickly and efficiently, without causing tissue damage or inhibiting the normal functioning of the body’s systems. However, this does not always occur—a variety of conditions result from excessive or chronic innate and inflammatory responses.
The most dangerous of these conditions is sepsis, a systemic response to infection that includes fever, elevated heartbeat and breathing rate, low blood pressure, and compromised organ function due to circulatory defects. Several hundred thousand cases of sepsis occur annually in the United States, with mortality rates ranging from 20% to 50%, but sepsis can lead to septic shock—circulatory and respiratory collapse that has a 90% mortality rate. Sepsis results from septicemia, infections of the blood, in particular those involving gram-negative bacteria such as Salmonella and E. coli, although other pathogens can also cause sepsis.
The major cause of sepsis from gram-negative bacteria is the cell wall component LPS (also known as endotoxin), which as we learned earlier is a ligand of TLR4. As we have seen, LPS is a highly potent inducer of innate immune mediators, including the proinflammatory cytokines TNF-α, IL-1β, and IL-6; chemokines; and antimicrobial components. Systemic infections activate PRRs on blood cells including monocytes and neutrophils, vascular endothelial cells, and resident macrophages and other cells in the spleen, liver, and other tissues, to release these soluble mediators. They, in turn, systemically activate vascular endothelial cells, inducing them to produce cytokines, chemokines, adhesion molecules, and clotting factors that amplify the inflammatory response. Enzymes and reactive oxidative species released by activated neutrophils and other cells damage the vasculature. This damage, together with TNF-α–induced vasodilation and increased vascular permeability, results in fluid loss into the tissues that lowers blood pressure. TNF also stimulates release of clotting factors by vascular endothelial cells; locally this helps to limit the spread of infections, but systemically it results in blood clotting in capillaries. These effects on the blood vessels are particularly damaging to the kidneys and lungs, which are highly vascularized. High circulating TNF-α and IL-1 levels also adversely affect the heart. Thus the systemic inflammatory response triggered by septicemia can lead to circulatory and respiratory failure, resulting in septic shock and death.
As high levels of circulating TNF-α and IL-1β are highly correlated with morbidity, considerable effort is being invested in developing treatments that block the adverse effects of these normally beneficial molecules. Neutralizing these cytokines in early sepsis may be helpful, but by 24 hours following onset of sepsis other factors, including IL-6 and chemokines, become more important. Much still needs to be learned about sepsis and septic shock to enable the development of effective treatments.
While not as immediately dangerous as septic shock, chronic inflammatory responses resulting from ongoing activation of innate immune responses can have adverse consequences for our health. For example, a toxin from Helicobacter pylori bacteria damages the stomach by disrupting the junctions between gastric epithelial cells and also induces chronic inflammation that has been implicated in peptic ulcers and stomach cancer. Cytokines produced by intestinal ILCs in response to infection can cause colitis. Also, increasing evidence suggests that the noninfectious DAMPs cholesterol (as insoluble aggregates or crystals) and b-amyloid contribute, respectively, to atherosclerosis (hardening of the arteries) and Alzheimer’s disease. Other examples of harmful sterile (noninfectious) inflammatory responses discussed earlier—including gout, asbestosis, silicosis, and aseptic osteolysis—are induced, respectively, by crystals of monosodium urate, asbestos, and silica, and by metal alloy particles from artificial joint prostheses. These varied substances are all potent inflammatory stimuli because of their shared ability to activate the NLRP3 inflammasome, resulting in the release of the proinflammatory cytokines IL-1β and IL-18. Additional examples of chronic inflammatory conditions will be presented in Chapter 15.
Innate immune responses play essential roles in eliminating infections, but they also can be harmful when not adequately controlled. It is therefore not surprising that many regulatory processes have evolved that either enhance or inhibit innate and inflammatory responses. These mechanisms control the induction, type, and duration of these responses, in most cases resulting in the elimination of an infection without damaging tissues or causing illness.
Innate and inflammatory responses are increased by a variety of mechanisms to enhance their protective functions. Signaling pathways downstream of multiple PRRs can work together to generate heightened responses. For example, in response to yeast, signaling pathways downstream of TLR2 and the CLR dectin-1 synergize to enhance protective cytokine production. Dengue virus RNA is recognized by TLR3, RIG-I, and MDA5, and signals from these three pathways synergize for heightened cytokine and IFN production. An important example, described earlier in this chapter, is the amplification of production of IL-1β and TNF-α, two of the initial cytokines induced by PAMP or DAMP binding to PRRs. As mentioned earlier, they activate pathways similar to those downstream of TLRs, and hence induce more of themselves, an example of positive feedback regulation.
On the other side of the equation, as uncontrolled innate and inflammatory responses can have adverse consequences, many negative feedback mechanisms are activated to limit these responses. Several proteins whose expression or activity is increased following PRR signaling feed back to inhibit steps in the signaling pathways downstream of the PRR. Examples include production of a short form of the adaptor MyD88 that inhibits normal MyD88 function; the activation of protein phosphatases that remove key activating phosphate groups on signaling intermediates; and the increased synthesis of IκB, the inhibitory subunit that keeps NF-κB in the cytoplasm. The activation of these and other intracellular negative feedback mechanisms can lead cells to become less responsive, limiting the extent of the innate immune response. In a well-studied example, when macrophages are exposed continuously to the TLR4 ligand LPS, their initial production of antimicrobial and proinflammatory mediators is followed by the induction of inhibitors (including IkB and the short form of MyD88) that block the macrophages from continuing to respond to LPS. This state of unresponsiveness, called LPS tolerance (or endotoxin tolerance), reduces the possibility that continued exposure to LPS from a bacterial infection will cause septic shock.
Other feedback pathways inhibit the inflammatory effects of TNF-α and IL-1β. Each of these cytokines induces production of a soluble version of its receptor or a receptor-like protein that binds the circulating cytokine molecules, preventing the cytokines from acting on other cells. In addition, the anti-inflammatory cytokine IL-10 is produced late in the macrophage response to PAMPs; it inhibits the production and effects of inflammatory cytokines and promotes wound healing.
In a recently described example, the induced production of IFN-β protects mice from the lethal hyperinflammatory effects of IL-1β during Streptococcus pyogenes infection. Following endocytosis by dendritic cells, S. pyogenes releases ribosomal RNA (rRNA), which binds to endosomal TLR13 and activates IFN-β production. The IFN-β binds to IFNAR on dendritic cells, macrophages, and neutrophils that have been activated by S. pyogenes PAMPs and reduces transcription of the IL-1 gene. This allows sufficient IL-1 to be produced to provide beneficial effects while avoiding excessive levels that would cause harmful hyperinflammatory responses.
However, these negative regulatory interactions sometimes may be disadvantageous. One example may explain how influenza virus infection causes increased susceptibility to bacterial infections that cause pneumonia. IRF3 activated by RLR signaling pathways triggered by influenza RNA binding reduces transcription of some cytokines normally induced by TLR signaling that promote protective antibacterial T-cell responses.
Many pathogens have evolved mechanisms that allow them to evade elimination by the immune system by inhibiting various innate and inflammatory signaling pathways and effector mechanisms that would otherwise clear them from the body. Most bacteria, viruses, and fungi replicate at high rates and, through mutation, may generate variants that are not recognized or eliminated by innate immune effector mechanisms. Other pathogens have evolved complex mechanisms that block normally effective innate clearance mechanisms. A strategy employed especially by viruses is to acquire genes from their hosts that function as inhibitors of innate and inflammatory responses. Examples of the wide range of mechanisms by which pathogens avoid detection by PRRs, activation of innate and inflammatory responses, or elimination by those responses are described in Table 4-7, and additional evasion mechanisms are presented in Chapter 17.
| Type of evasion | Examples |
|---|---|
Avoid detection by PRRs |
Flagellin of proteobacteria has a mutation that prevents it from being recognized by TLR5 Helicobacter, Coxiella, and Legionella bacteria have altered LPS that is not recognized by TLR4 HTLV-1 virus p30 protein inhibits transcription and expression of TLR4 Several viruses (Ebola, influenza, vaccinia) encode proteins that bind cytosolic viral dsRNA and prevent it from binding and activating RLR |
Block PRR signaling pathways, preventing activation of responses |
Vaccinia virus protein A46R and several bacterial proteins have TIR domains that block MyD88 and TRIF from binding to TLRs Several viruses block TBK1/IKK activation of IRF3 and IRF7, required for IFN production West Nile virus NS1 protein inhibits NF-κB and IRF transport into the nucleus Yersinia bacteria produce Yop proteins that inhibit inflammasome activity; the YopP protein inhibits transcription of the IL-1 gene |
Prevent killing or replication inhibition |
Listeria bacteria rupture the phagosome membrane and escape to the cytosol Mycobacterium tuberculosis blocks phagosome fusion with lysosomes and inhibits phagosome acidification M. tuberculosis and Staphylococcus aureus produce proteins that protect them from ROS and RNS Vaccinia virus encodes a protein that binds to type I IFNs and prevents them from binding to the IFN receptor Ebola virus blocks the antiviral effects of IFN by preventing the nuclear translocation of phosphorylated STAT1 Hepatitis C virus protein NS3-4A and vaccinia virus protein E3L bind protein kinase R and block IFN-mediated inhibition of protein synthesis Herpesvirus and poxvirus encode versions of the anti-inflammatory cytokine IL-10 that reduces the local inflammatory response and T-cell activation |