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It's Complicated: Inflammation from Metchnikoff to Meryl Streep

2010; Wiley; Volume: 24; Issue: 11 Linguagem: Inglês

10.1096/fj.10-1101ufm

1530-6860

Gerald Weissmann,

Shakespeare, Adaptation, and Literary Criticism

In “It's Complicated” Ms. Meyers transforms a divorced couple into a romantic couple, which suggests a belief in love enduring even after a marriage dies. That sounds wonderfully romantic or a prescription for pathology, maybe both. [But] she wants, as her title implies, to complicate that formula. We have met the enemy, Ms. Meyers seems to be suggesting, and she is firmer—and younger. But infection also has its counter. The attacked organism defends itself against the little aggressor. It protects itself by all the means at its disposal to destroy the invader. The organism digests substances introduced outside the digestive tract by means of an inflammatory response. The end result of inflammation [often] is not defense; it is an agitated committee-directed, harum-scarum effort to make war, with results that are remarkably like those sometimes observed in human affairs. One doesn't usually come away from a Hollywood flick with thoughts of Metchnikoff and inflammation. On the other hand, “It's Complicated” features each of the cardinal signs of inflammation: redness and swelling with heat and pain, leading to loss of function. It also shows an attacked organism defending itself against a little aggressor. The film is set in Boniva/Viagra-land, in which a divorced couple (Meryl Streep and Alec Baldwin) catch up with each other after 15 years apart. Streep's in pain: their three grown kids have left the nest empty, and Baldwin's married to a hot, young chick. The couple meets up to celebrate their son's college graduation. They lose composure at a bibulous function. Streep turns red, and Baldwin prances. Sure enough, they wind up in bed. Back home, Streep's circle swells: the kids return with significant others, the firm, young chick has a lovable kid of her own, and then there's Steve Martin, to whom Streep is loosely attached. Agitated, harum-scarum efforts (à la Thomas) are launched; action and reaction follow. But, at last, the empty nest becomes a love nest when Streep and Martin exit laughing as the final credits roll. The end of this so-so film pays tribute to a hot, new area of experimental biology: the resolution of inflammation. (4) The literature is awash in inflammation these days (Table 1). I'm sure that we apply the term much too loosely. Every condition in which someone's humor goes awry, or a cell waxes wroth is chalked up, willynilly, to “inflammation”. A glance at Table 1 shows that inflammation has been held responsible for aging and obesity, depression and cancer, not to speak of osteoporosis and erectile dysfunction. It's complicated—too complicated, perhaps. Most of these papers simply describe that one or another cell has made or responded to one or another mediator of inflammation. So perhaps we'd better go back to the original definition of inflammation and to its original cause: the battle between a host and an army of microbes. Redness and swelling with heat and pain—rubor et tumor cum calore et dolore—have been recognized as the four cardinal signs of inflammation since the writings of Aulus Cornelius Celsus (c.25 B.C.–c.50 A.D.). The fifth—functio laesa (loss of function)—was added by Rudolf Virchow in 1858. (5) Doyens of the field agree that although one can have one or another of these signs without inflammation, it ain't inflammation until one has at least four. (6) Emotions, such as turning crimson like Streep ogling Baldwin or pining in pain like a flummoxed Steve Martin, are not inflammation. But, if you've caught a bad strep in your throat or been stung by a wasp on your eyelid, only then are you inflamed: you've seen redness and swelling with heat and pain first-hand. As for functio laesa, call your doctor. We've learned recently that our brigades of ILs, IFNs, and inflammasomes respond to levels of cellular concern that wouldn't raise a small pimple on the chin. (7, 8) So, let's watch our language and not cry inflammation whenever one or another cytokine cries for attention from its array on the chip. On the other hand, what if Metchnikoff's little aggressors, the microbes, really are responsible for conditions that rank near the top of the list in Table 1? Isn't human papilloma virus infection related to cancer? (9) Hasn't rheumatoid arthritis been linked to porphyromonas gingivalis? (10) Aren't Chlamydia pneumoniae found in the lesions of atherosclerosis? (11) It's complicated. It may be a stretch to extract classic pathology from the plot of a Hollywood film, but not the other way around. For me, the classic accounts of inflammation spin a tale more artful than any recent film of Streep's. In its simple, concise expression, Celsus's rubor et tumor cum calore et dolore owes much to artful poet Horace, whose Nullius addictus iurare in verba magistri (I am not bound over to swear allegiance to any master) became the motto of the Royal Society. (12) Celsus, who is sometimes confused with Anders Celsius of thermometry (1701–1744), was describing the typical reaction of flesh to microbes, not, as nowadays, the increase of a mediator or cytokine of some type. Indeed, evolutionary biology teaches that although inflammation may help the individual cope with cuts and bruises, it was primarily designed to protect the species from lethal epidemics. By 1905, when Robert Koch was awarded his Nobel Prize for spotting the agents of anthrax and tuberculosis, it became evident that inflammation served to defend us against microbes, not miasmas. Three years later, Nobel Prizes were awarded to Paul Ehrlich for his work on humoral immunity (antibodies) and to Elie Metchnikoff for his work on cellular immunity (phagocytosis). Their work established that the body uses both strategies to identify and destroy microbial invaders. In the battle against infection, we call our losses “infection” and our victories “immunity.” When the aggressor in this struggle is much smaller than its adversary the result is that the former introduces itself into the body of the latter and destroys it by means of infection … But infection also has its counter. The attacked organism defends itself against the little aggressor. It protects itself by interposing a resistant membrane, or it uses all the means at its disposal to destroy the invader. (2) The major “means at its disposal” was the arousal of phagocytes (or “eating cell”, which was Metchnikoff's term). The phagocyte engulfs the invaders in a resistant membrane (now, a phagolysosome) and digests them within the vacuole by means of cytases (lysosomal enzymes). When these enzymes are mistakenly released into tissues, inflammation results. (13) Many of us remain convinced that this mechanism lies at the root (literally) of inflammation in several common conditions, but again, it's complicated. To many, the situation here encountered resembles a battlefield on which the leukocytes meet the invading bacteria and contest their further increase and invasion until they triumph, and, the infection overcome, the inflammation subsides. (14) “… le principe fondamental de toute guerre coloniale est que l'Européen soit supérieur au peuple qu'il combat.” The diapedesis of the white corpuscles, their migration through the vessel wall … is one of the principal means of defense possessed by an animal. As soon as the infective agents have penetrated into the body, a whole army of white corpuscles proceeds towards the menaced spot, there entering into a struggle with the micro organisms. The leukocytes, having arrived at the spot where the intruders are found, seize them after the manner of the Amoeba and within their bodies subject them to intracellular digestion. (2) Corpora non agunt nisi fixata. Cellulare non agunt nisi fixata. Paul Ehrlich and his contemporaries were sure that the body had a horror autotoxicus—an incapacity to turn its defensive weapons into tools of self-destruction. But, time and events have overturned that conviction. In the 1950s, Roitt and Doniach, among others, proposed the notion of autoimmunity: inflammation in the thyroid was caused by antibodies directed against a self-antigen. (17) Horror, indeed! Since then, we learned that the tools of acquired immunity as well as those of innate immunity can be self-destructive. Counter-insurgency can lead to self-injury. Divorce hurts, as Streep explains in the film. We have unearthed an array of unlimited weapons for warfare against the invisible armies of microbes, and each of them can be turned back on our own tissues. Our cells in battle are bathed by components of complement—that extracellular pattern recognition system—with which they can react to pro-and anti-inflammatory eicosanoids; pro-and anti-inflammatory ILs; immune and nonimmune IFNs, and signals from T helper and suppressor lymphocytes. They respond with pro- and anti-inflammatory signaling cascades that trigger the JAKs and the STATs, the NF-κBs, and so forth and so on. The collateral damage we inflict is often to ourselves. (7, 8, 18) I suspect that the host is caught up in mistaken, inappropriate, and unquestionably self-destructive mechanisms by the very multiplicity of defenses available to him, defenses which do not seem to have been designed to operate in net coordination with each other…. If, to push the analogy, there were no limit to the number of people who could set off for northern Minnesota at the season of the great fly-over of geese and no limit on the type and power of the weapons to be used by each, we would undoubtedly observe, what with M-16's, howitzers, SAM missiles, lasers, and perhaps tactical nuclear rockets, considerably more destruction of people than geese, of host than invader. (3) It's complicated.