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Imagine that you're a neutrophil speeding through the blood. According to Sompayrac's book (page 18), you're moving at about 1 millimeter per second, astonishingly fast for something so small. As you're swept along, you're on the lookout for invaders. Your lifetime is pretty short, only a few days, so you better make use of the time that you're allotted. But you needn't worry. You're accompanied by many, many similar cells each with the same mission. You're looking out for threats. But if something bad happens, how do you slow down, stop, and leave the bloodstream to take action against predators? From what I've been able to learn, this process is complicated (as are most of the other processes in both innate and adaptive immunity). The first step appears to be the release of two cytokines by tissue macrophages and other cells (I'll discuss another important sentinel cell in an upcoming post) upon detection of a pathogen. These two, Interleukin-1 and tumor necrosis factor may not be the only ones involved in the process of slowing neutrophils, but they're the main ones elicited by macrophages according to my sources. These cytokines send a signal to other cells (remember, that's what cytokines do). In particular, they tell the cells that line nearby capillaries and small veins (endothelial cells) that something is amiss and that they should express a protein that binds to structures that found on the surface of the neutrophil. That protein is called "selectin". OK. I promised that I'd be light on the nomenclature and jargon. And here I've introduced four terms: "interleukin-1", "tumor necrosis factor", "endothelial cells", and "selectin" in one paragraph. It's unfortunate, but these entities have names. You don't have to memorize them, but it's easier for me to refer to them by their names as apposed to describing what they do every time I mention them. Beware, there'll be more names to come. But at least I've avoided abbreviations!  As I've tried to show in the cartoon above, the selectin on the surface of the capillary lining cells interacts with its complement on the surface of the neutrophil. The bond they form is weak and transient. When it breaks, another forms with a downstream endothelial cell. The neutrophil "rolls" from one toehold to another, slowing down as it does so. It is this rolling slow motion that allows it to respond to other signals that emanate from an inflamed site. The reaction of the neutrophil? It rapidly activates a protein called "integrin" that is already present on its surface, but in an inactive form. The activation increases the affinity of the integrin for its complement (the intercellular adhesion molecule in the cartoon above) found on the surface of the endothelium. The result is that the neutrophil comes to a stop.
Once immobile another complex series of reactions occurs that allows the neutrophil to escape the blood vessels in which they've been immersed and to infiltrate the tissue under attack. Upon arrival there they become killing machines. As mentioned in the last post, they are super destructive cells, swallowing up invaders with deadly efficiency, releasing cytokines that recruit other neutrophils to the site of inflammation, secreting a toxic mix of proteins and enzymes that kill and digest, and forming a net using DNA strands to trap microbes. It appears that other immune cells that must leave the blood stream and enter tissues use the same mechanism to slow and stop. These include some of the cells of the adaptive immune system that we'll discuss later. Since there are many distinct selectins and integrins, the body can precisely call upon the appropriate cells to respond to the particular attack that occurs. Once an attack by neutrophils has begun it's important that it doesn't get out of hand. There's a nice summary of the consequences of chronic inflammation here. I quote from the first paragraph of the article: "The inflammatory response must be constantly constrained to prevent molecular, cellular and organ damage. The consequences of unregulated inflammation are associated with, or directly underpin, a substantial fraction of diseases that plague us, including autoimmune and metabolic diseases, infectious diseases caused by large macroparasites to viruses, chronic neurological diseases, malignancy and life-threatening acute responses to pathogen products such as sepsis and shock. Correspondingly, a proportionate percentage of the modern pharmacopoeia is devoted to blocking inflammation, from widely used drugs such as aspirin and the non-steroidal anti-inflammatory medication to humanized anti-cytokine antibodies." One way that the damage of an overactive innate response is limited is that neutrophils, which can do the most damage, have a short life span, only a few days. Another tactic that the body uses is to make use of inhibitory cytokines. There appear to be many of these, too many to recount here. Some act to restrict the immune response by inhibiting the production of the cytokines that excite it in the first place. Others bind to the same sites as their excitatory counterparts, but don't elicit a response. Still others are released by the contents of dying cells. From what I've read, a lot is still to be learned about this area, and the mechanisms that limit the innate response are under active investigation in a number of laboratories. Despite my efforts to simplify, it should be clear from what I've written so far that the innate response is byzantine, with many positive and negative players, all interacting in a great variety of ways. But there's much more to innate immunity. I'll start to describe these additional components in the next post.
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