Hello, I'm Peter Libby from Boston's Brigham and Women's Hospital and Harvard Medical School. And I'm pleased to participate in this symposium called Inflammation: The next therapeutic frontier in confronting residual cardiovascular risk. My role, in a few introductory comments, is to talk about immunity and inflammation in atherosclerosis, no longer just a theory. These are my competing interests.

When I started out in atherosclerosis research the pioneer of cell biology of atherosclerosis was Russell Ross and he focused appropriately on the proliferation of smooth muscle cells that followed denuding endothelial injury. This was his original conception of the response to injury hypothesis of atherosclerosis. I want to call your attention to the complete absence of inflammatory cells or any signs of inflammation in this original construction of Professor Ross's.

Well, there were a few of us renegades, back in the 1980s who were interested in the inflammatory aspects of atherosclerosis as you'll hear from Professor Lüscher. We really just closely read what Virchow talked about in the mid-19th century. So my colleague Professor Johan Hansson working in Sweden was focused on T-cells and their effects on the vascular wall cells and in my laboratory in Boston we were interested in pro-inflammatory cytokines as mediators of conversations between leukocytes and the vascular wall cells that could give rise to disease. Over 30 years ago we published this early review about involvement of the immune system in human atherosclerosis and current knowledge in unanswered questions. So we've gained a lot of knowledge in the last 30 years but we still have a lot of unanswered questions as we will hear throughout this symposium.

So the fundamental observation was that early on after exposure to classical risk factors such as hypercholesterolemia, leukocytes enter the arterial intima and there they can release mediators to change the behavior of the endothelial cells to recruit more leukocytes and instigate the migration and proliferation of smooth muscle cells as was noted by Russell Ross back in the 1970s. Ultimately plaques become complicated and will lead to clinical events most dramatically through plaque disruption and thrombosis which cause acute myocardial infarction and other acute coronary syndromes.

My laboratory, through the decades, was trying to take apart the cell and molecular biology of inflammation in the atherosclerotic plaque. Back in 1986, we discovered that human vascular cells endothelial cells are shown in panel A here and smooth muscle cells, not shown could inducably express the messenger RNA, encoding IL-1β a primordial pro-inflammatory cytokine. We also showed that the biological activity and the protein were expressed inducably. We then, in 1987, together with Charles Dinarello, the pioneer of interleukin-1β biology, discovered that IL-1 can reduce its own gene expression. That provides an amplification loop. Autoinduction. We then soon afterwards found that IL-1 can reduce another pro-inflammatory cytokine about which we'll be hearing much more in this series of lectures: interleukin 6. A little bit of interleukin-1α as you see in panel C can cause smooth muscle cells or endothelial cells to pour out a lot of this messenger cytokine, and I'll explain that in a moment. In 1995 we found that the enzyme that converts the inactive precursor of interleukin-1β to its active form, Caspase-1, is expressed in human atherosclerotic plaques, as you see here in the foam cell and then in 1997 we were able to show processing of pro-IL-1β which is on the left side of panel D, to the active form which appears with time of incubation with a pro-inflammatory cytokine CD40 ligand that we knew even back in 1997, was operating in atherosclerosis.

So, just to sum up this pathway, which we've been working on for decades. The inflammasome can activate the precursor of interleukin-1β then IL-1 can induce its own gene expression, amplification loop no. 1. Then IL-1 can induce a lot of IL-6, amplification loop no. 2. IL-6 we called the messenger cytokine because it tells the hepatocyte to rev up the synthesis of acute phase reactants. We measure this acute phase response by C-reactive protein and dr. Ridker and dr. Crea will talk about that. Also part of the acute phase response is elaboration by the hepatocyte of fibrinogen, the precursor of clots, and the major blocker of our own clot-busting system, our own fibrinolytic system: Plasminogen activator inhibitor-1.

What is actually turning on this inflammatory response? I already mentioned hypercholesterolemia, but hypertension, cigarette smoking, diabetes your traditional risk factors are all associated with pro-inflammatory stimuli, but then there are the emerging non-standard risk factors, such as hypertriglyceridemia or triglyceride-rich lipoproteins, adipose tissue, particularly, visceral adipose tissue or ectopic adipose tissue, about which you'll be hearing, which can invest the adventitia of arteries. There's a great deal of interest in the microbiome as an aggravator of atherogenesis. And then the new kid on the block is clonal hematopoiesis which is a recently described aggravator of atherosclerosis risk.

So, where do we stand in taking this science and translating it to patients? Which is really the subject of this symposium. It takes 80 milliseconds to find 1.7 million references about inflammation and atherosclerosis. And it takes 80 milliseconds to come up with a little over a quarter of a million references on immunology and atherosclerosis.

But all of the basic science work really is for naught unless we can translate our in vitro work in animal experiments to humans. And that's really what we're about in this symposium.

Can targeted anti-inflammatory therapy improve cardiovascular outcomes in humans? The subsequent talks in this series will deal in detail with this conjecture.

I'd like to close by acknowledging the people who've helped us in our basic science laboratory here. We're finishing a big experiment together in the days of COVID-19.

And this is a list of some of my key collaborators including Professor Paul Ridker who will be speaking in this series. Thank you very much.

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