IT IS as if more and more evidence had begun to accumulate implicating the same person in numerous different murders – yet they had no apparent motive and had hitherto been considered innocent. Most detectives would try to tease out any common thread that tied the crimes together and link them to the suspect.
So, too, in medical research. When the same biological signature turns up in conditions as diverse as rheumatoid arthritis, heart attacks, Alzheimer’s disease and cancer, it is time to take a closer look. In each case the suspect is inflammation – the familiar immune response that causes the redness, swelling, pain and sometimes pus if you graze your knee, sprain your ankle or sprout a pimple.
Inflammation is known to play a role in diseases that involve an overactive immune system, such as asthma, allergies and autoimmune conditions like rheumatoid arthritis. But barely a month goes by now without researchers announcing fresh evidence implicating the cells and chemicals of the inflammatory response in some new disease.
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So what is going on? Have we misunderstood the role of inflammation in the body all this time? Is there some factor that links all these diseases together?
The mystery has not yet been solved, but as a growing number of researchers in different specialties are focusing their efforts on the same area, important insights are emerging. The explanation may be simply that while the conditions have different causes, and involve diverse organs and tissues, the inflammatory response helps perpetuate the disease process. In some cases, we’ve begun to work out why – something goes wrong with the normal signals that call off the inflammatory response. Inflammation is not the cause of all these diseases, it turns out – but it may help some of them persist.
This new realisation has opened the door to a host of treatment strategies. Existing anti-inflammatory medicines may be put to unexpected new use. And novel drugs that can tame persistent inflammation could be wonderfully versatile, finding applications in both newly discovered and “conventional” inflammatory diseases. “If we could start developing [such] drugs it could be a very big thing,” says Derek Gilroy, a pharmacologist and inflammation expert at St Bartholomew’s Hospital in London. “It has a great deal of potential.”
The new take on inflammation is all the more surprising because the mechanisms behind this biological process have been known for decades. After a scrape or knock, or an invasion by viruses or bacteria, nearby cells send out chemical signals, or cytokines, that increase blood flow to the area and recruit immune cells complete with their formidable array of chemical weapons. In contrast to the second-line “adaptive” immune response, which involves antibodies and immune cells directed against specific foreign proteins, this first-line reaction is immediate and indiscriminate.
That means the inflammatory cells can harm innocent bystanders. “They can inflict friendly-fire damage on tissues,” says John Savill of the University of Edinburgh’s Centre for Inflammation Research. If the inflammation is short-lived, such damage is usually negligible. But sometimes the inflammation doesn’t die away quickly, and that’s when the serious problems start. “A long-forgotten injury gives rise to a persistent inflammation response that’s now dangerous,” he says. “It becomes a cause in itself of disease.”
Perhaps the best example is the role of chronic inflammation in heart disease (Â鶹´«Ă˝, 11 January 2003, p 36). The conventional view was that this common condition was analogous to a plumbing problem. High blood cholesterol levels caused fatty plaques to build up inside artery walls, limiting the blood supply to the heart. And if the plaque disintegrated and caused a blockage in narrower vessels downstream, this could trigger a heart attack. The new thinking, however, is that while these processes play their part, inflammation of the artery walls is another factor, which causes the plaque both to build up and to disintegrate.
The part inflammation plays in other conditions may be less clear-cut, but the circumstantial evidence for an important role is certainly compelling. Take Alzheimer’s disease: this has long been thought to be caused by clumps of a protein called beta-amyloid building up in the brain. But since the early 1990s doctors have been intrigued by the fact that arthritis patients who take anti-inflammatory painkillers known as NSAIDs for many years are less prone to Alzheimer’s. Inflammatory cells have also been found in the brains of people with this form of dementia.
The link between inflammation and cancer is longer established, although just as muddy. At least three types of tumours – colon, liver and lung – often start at sites of chronic inflammation. And again, people taking NSAIDs over many years are less likely to get colon or breast cancer. NSAIDs work by inhibiting COX-2, a key intracellular enzyme involved in inflammation and pain. COX-2 has been found to occur at higher levels in most human breast cancers, but the enzyme has many effects and it is unclear which is most important in promoting tumour growth.
So what could be causing the inflammation to persist in all these diverse diseases? Until recently, most scientists put long-term inflammation down to some sort of lingering alarm signal that kept calling out the troops. A persistent infection could be responsible, say, or, in the case of autoimmune diseases, mistaken recognition of one of the body’s own proteins as foreign. Immunologists assumed that without the alarm call, the inflammation would just fizzle out. That assumption turns out to be wrong.
The first signs that something more interesting was going on came about a decade ago. A team headed by Charles Serhan, a biochemist at Harvard Medical School, was studying the chemical signals involved in triggering inflammation in mice when they found something that did not fit. One class of molecules they came across, called lipoxins, recruits precursors of immune cells called macrophages, which devour bacteria, dying cells and debris. But instead of bringing in the macrophages primed and ready for battle, the lipoxins pacified them and stopped them from perpetuating the inflammatory response.
Serhan’s group began studying this curious peacenik behaviour more carefully. In time they discovered an intricate network of signalling molecules whose role is to damp down, or resolve, inflammation. One class of these signals, which Serhan dubbed “resolvins”, turned out to be derivatives of omega-3 fatty acids, which may help explain why a diet rich in these fats cuts the risk of heart disease. “That was completely unexpected,” says Serhan.
Now that Serhan had shown that resolving inflammation was an active process, not just a default pathway, it made more sense to ask why resolution sometimes fails. After all, in most people, inflammation normally dies down in a few days. If it didn’t, every thorn-prick would be a catastrophe. “That has been the $64,000 question in inflammatory disease,” says Savill. “It isn’t obvious why some inflammations resolve and others persist.”
An important factor, Savill says, could be the kind of funeral given to the immune cells called neutrophils that flood in during inflammation. If all goes well, these cells die within two or three days in a carefully controlled process known as apoptosis, and are eaten by macrophages before their contents escape. Neutrophils undergoing apoptosis display a special chemical on their cell surface called phosphatidylserine (PS), which triggers the macrophages to release cytokines such as transforming growth factor beta (TGF-beta) that actively promote resolution.
But sometimes neutrophils get a different sort of send-off. If for some reason the apoptosis program fails, they die a messier death, known as necrosis. Lacking the PS signal, macrophages fail to eat them in time, and their contents, including pro-inflammatory cytokines, leak away. And macrophages that clear up their remains release a key pro-inflammatory cytokine, tumour-necrosis factor alpha (TNF-alpha). “It’s a double whammy of anti-inflammatory events,” says Gilroy.
So what signs are there that these processes play a role in human diseases involving persistent inflammation? Perhaps the best evidence is in the autoimmune disease rheumatoid arthritis, which has a major inflammatory component. A team led by Chris Buckley and Mike Salmon, rheumatologists at the University of Birmingham in the UK, thinks that the key problem is with resolution of inflammation. In the chemical crosstalk within rheumatoid joints, an excess of a cytokine called CXCL12 helps dissuade the inflammatory immune cells from undergoing apoptosis. Instead, they hang around – and, says Buckley, “the conversation starts to get dangerous”. The chemical milieu of the joints starts to resemble that of lymph nodes, the glands in the body where immune cells are sent after fighting off infections and where they act as our immunological memory. Buckley’s team has found over the past few years that in rheumatoid arthritis, large numbers of immune cells treat the joint itself as a hyperactive lymph node, setting up permanent inflammation that gradually erodes the cartilage.
Problems with the resolution of inflammation also appear to play a role in another autoimmune disease, systemic lupus erythematosis, or lupus for short, although in this case the target of the immune attack is unknown. In healthy people, apoptotic cells are normally cleared away so fast you never find them lying around. But two years ago Martin Herrmann, an immunologist at the University of Erlangen-Nuremberg in Germany, found them in several tissues. “Wherever you look, you see more apoptotic cells lying around than normal,” he says.
Moreover, people with a rare genetic defect that leaves them unable to make a protein called C1q – a bridge molecule that helps scavenging cells latch onto their apoptotic prey – almost always develop lupus.
Crucially, it is not only the conventional inflammatory diseases where these molecular pathways seem to play a role. In heart disease, the plaques that line artery walls are full of the debris of apoptotic cells. And a team led by Martin Bennett, a cardiologist at Addenbrooke’s Hospital in Cambridge, UK, showed a few years ago that scavenging cells such as macrophages in plaques recognise the PS signal that triggers apoptosis. So why doesn’t the apoptosis process help the inflammation resolve? It is now known that the oxidised lipids present in the plaque can bind to PS receptors on scavenging cells, which, theoretically at least, could prevent clearance of the apoptotic cells, says Bennett.
The relevance of this work to other diseases is still unknown. But this growing understanding of the importance of resolution offers scientists a second front in the fight against diseases that involve chronic inflammation – whether or not failure of resolution is where the primary defect lies. And if existing anti-inflammatory drugs are anything to go by, they could prove incredibly versatile.
Current anti-inflammatories target the other end of the process – the signals that trigger inflammation. Recently, for example, drugs that target TNF-alpha have shown promise against a wide range of inflammatory diseases such as rheumatoid arthritis, psoriasis and severe forms of asthma. TNF-alpha is one of the first and loudest chemical alarms to sound during injury or infection, and plays a key role in starting and maintaining inflammation. The new drugs block this signal, dramatically reducing inflammatory symptoms. Unfortunately, they don’t cure the disease – symptoms return as soon as patients stop taking the drugs.
And there is another problem with anti-TNF drugs and other existing anti-inflammatories: inflammation, in most cases, is a good thing. It helps repel invading microbes and cope with the many injuries, large and small, that strike in the course of daily life. Drugs that prevent inflammation from starting tamper with this defence and can leave patients vulnerable to infections.
Drugs aimed at enhancing the resolution phase, on the other hand, would in the main preserve the immune system’s rapid response to injury or invasion, while ensuring that inflammation gets turned off once that task is accomplished. “They shouldn’t affect the onset phase, which is a good thing,” says Gilroy. “It may be a clearer way of allowing the immune system to do its job and then switching it off when it has to.”
And the success of anti-TNF drugs in treating a wide variety of inflammatory diseases suggests that pro-resolution drugs would have similarly wide success. However, the whole concept of active resolution is new enough that researchers have not yet developed or tested such medicines. Indeed, they may not be simple to design. “You’re trying to enhance something, not inhibit it,” says Henson. “That’s not so easy.”
A few hints of success have emerged, though. Serhan’s group found two years ago that when mice with asthma were exposed to allergy triggers, the cells lining their airways pumped out more lipoxin, LXA4, to damp down the inflammation. Giving artificial LXA4 boosted this natural resolving mechanism, reducing inflammation and opening the airways of the mice (Nature Medicine, vol 8, p 1018). Mice genetically engineered to carry the human receptor for LXA4 showed a similar improvement, suggesting that the therapy could work in people as well.
Helping macrophages clear away apoptotic cells from the site of inflammation could also improve resolution. Herrmann is now doing test-tube studies to see whether two signalling molecules, GCSF and GMCSF, will make macrophages more willing to eat up apoptotic cells and favour resolution. Savill, too, is looking at drugs to enhance apoptotic clearance, but he says the work is at too early a stage to discuss as yet.
Of course, pro-resolution drugs could have side effects. For example, the pro-resolution TGF-beta produced by macrophages can promote scarring – an appropriate response after tissue injury. But scarring is a serious problem – sometimes the most serious – in inflammatory diseases of the nervous system and lungs.
A second downside is that they could theoretically leave people more vulnerable to parasites. Many parasites evade the immune system in part by sending out their own resolution signals. For example, Trypanosoma cruzi, the organism that causes Chagas’ disease, triggers apoptosis of immune cells, perhaps using their pro-resolution effect to lull the immune system into inaction. And malaria parasites prompt infected red blood cells to display on their surface the PS signal normally used by inflammatory cells undergoing apoptosis. This, again, may pacify the immune system and may help explain why anti-malarial vaccines have been so hard to develop, says Herrmann.
Even the staunchest advocates of the pro-resolution approach admit it has its limits. “I don’t think it is the be-all and end-all,” says Serhan. Some persistent inflammation will no doubt turn out to be the result of a persistent stimulus. This could be a long-term infection, or it could happen when the immune system mistakenly identifies one of the body’s own proteins as foreign and attacks it, as in type 1 diabetes. Even there, however, Gilroy thinks pro-resolution drugs could help. “We could trick an ongoing inflammation into thinking it sees resolving signals and switching off.”
Immunologists have a lot more work to do in figuring out how the various resolution signals fit together to halt inflammation. And it will be years before they know for sure whether enhancing these signals will produce safe and effective medicines. But the evidence is certainly pointing that way.
This is one murder mystery that could be an open-and-shut case.
