NCI Keynote Address by David Spiegel
Dr. Spiegel presented on Circadian Cortisol Rhythms, Depression and Cancer Survival: Timing is Everything. One issue discussed is that because symptoms of cancer and cancer treatment overlap with depression, depression may be under-diagnosed (and consequently under treated) in patients with cancer. Depression is a concern both because of diminished quality of life, but also because there is data suggesting that depressed cancer patients are at increased risk for mortality, or conversely have lower survival times.
Specifically, although there is little evidence currently to suggest that depression is associated with cancer incidence, there is evidence that is predicts poorer prognosis and faster progression. Depressed cancer patients typically evidence disregulated cortisol rhythms (i.e., they do not exhibit the usual circadian rhythm). This may be due to an impaired ability to shut off cortisol (glucocorticoid) production. Although there does not seem to be experimental data yet, in a number of observational studies, beta-blockers seem to confer protection against decreased survival in depressed cancer patients supporting the beta-adrenergic pathway as a relevant mechanism linking depression to cancer progression and mortality. Depression may be under-diagnosed in cancer patients; however, there is also a growing body of evidence to suggest that cancer and cancer treatment may induce depression via inflammatory processes (other presentations also touched on this topic).
Presidential Symposium: Endogenous PAMPs, DAMPs, and Sterile Inflammation
This symposium included IL-1, Inflammasomes and the Sterile Inflammatory Response by Kenneth Rock and MAMPs, DAMPs, Inflammasomes and the Stress-Evoked Cytokine Storm by Monika Fleshner. I had always thought of inflammation in terms of the immune response to a pathogen or infection. I enjoyed this symposium because I learned about sterile inflammation: when inflammation occurs without infection. For example, Dr. Rock talked about how sterile cell death leads to an immune response and inflammation. However, without the interleukin 1 receptor (IL-1R), sterile cell death does not lead to inflammation. A series of experiments examining these pathways suggested a pathway that cell death leads to macrophages responding by secreting IL-1, which binds to IL-1R leading to inflammation. In an infectious model, macrophages are activated by ingesting (“eating” as their Greek name) pathogens, recognizing non-self and responding by secreting inflammatory cytokines (such as IL-1). However, in cell death, there are no infectious agents per se, so how do the macrophages detect or sense cell death? This seems to be via damage (or danger) associated molecular patterns (DAMPs). DAMPs come from dead cells with examples being uric acid, ATP, and complement. Macrophages sense many different kinds of DAMPs and IL-1 seems like a common pathway. The reason may be because when ingested, DAMPs actually cause damage internally to the macrophage. Thus the macrophage does not need to directly detect all the different types of DAMPs, it just needs to detect the results of DAMPs. This process can be inhibited by knocking out NLRP3 suggesting it is an important player (there were some nice diagrams that demonstrated the entire pathway much better than I can describe in words). Also discussed was how macrophages created pro-IL-1, but to become active, in needs to be cleaved by inflammasones (such as caspase 1) into IL-1 to be functional (this was also discussed in various other talks throughout the conference). The disease example of this process given was atherosclerosis. Damage to cells in the blood vessels can trigger sterile inflammation, and there was interesting data that a high fat diet was only problematic in rodent models when there was associated inflammation. That is, atherosclerosis seemed to be a combination of damage and the inflammatory response to really make the plaque and be problematic. Cholesterol crystals act as DAMPs, and data suggest atherosclerosis may be a crystal based disease.
Dr. Fleshner talked about the “inflammatory storm” caused by microbial associated molecular patterns (MAMPs; which she uses to distinguish from pathogen associated molecular patterns, or PAMPs, because they do not necessarily involve something foreign). She presented data on experiments where animals were exposed to a stressor (inescapable tail shocks) and the time course of IL-1β, IL-6, IL-10, and IL-18. Activation of the SNS, lead to the “cytokine storm” and then MAMPs and DAMPs. Giving mice a caspase (an inflammasome) inhibitor blocked this effect, suggesting that inflammasomes mediate the pathway between stress and MAMPs/DAMPs.
There was another presentation by Francisco Quintana from Harvard titled, Aryl hydrocarbon receptor (AHR) in the Control of Neuroinflammation, but it was too detailed for me to really follow and make much sense of. Apparently they can do some pretty cool things with nanoparticles to deliver certain molecules into a system (which was not the main focus of the talk, but I thought sounded cool).
The key points I felt I learned from this symposium were that sterile inflammation can occur without infection. This is related to things called DAMPs, PAMPs, and MAMPs, seems to be largely mediated via IL-1, which requires inflammasomes, so inflammasome inhibitors (such as inhibitors of caspase) can knockout the effects.
Glucocorticoids: Newly discovered functions in health and disease?
We typically think of glucocorticoids (GCs) as anti-inflammatory (in clinical practice dexamethasone, a potent glucocorticoid, is often used as an anti-inflammatory). In this session, Steven Maier (Glucocorticoids Can Be Pro-Inflammatory) and J. L. Eddy (Chronic Exposure to Glucocorticoids Primes an Epigenetic Proinflammatory Signature in Lymphocytes) presented data suggesting that glucocorticoids can be proinflammatory in certain conditions. Dr. Maier presented data suggesting that in a time course, glucocorticoids are anti-inflammatory at first (which makes theoretical sense as it brings down an inflammatory response), but later (roughly a day later) actually potentiates an inflammatory response. This is when typical physiological levels of glucocorticoids are administered, not when clinical doses (which are far higher than usually released after a stress response) are administered. GCs appear to potentiate an inflammatory response after 24 hours in part via sensitizing microglia which leads to increased inflammation in response to stress. After the presentation, there was one question/comment where the person seemed quite critical of the data and ideas presented, but it was not clear to me exactly why or how valid/invalid the argument was.
The oral session included two other talks, one by Carmine Pariante focusing on glucocorticoid receptors and one by Annemieke Kavelaars showing data that baseline GC sensitivity in leukocytes predicts post traumatic stress disorder (PTSD) symptoms after military personnel return from deployment. This may help target interventions or extra support to personnel particularly at risk for PTSD both in a military context and other situations where PTSD frequently occurs. For me, one implication from this session is that when evaluating and hypothesizing about the effects of glucocorticoids (in humans cortisol), it is paramount to consider the time course and when the stressor (or release of GCs) occurred relative to the effects you are interested in. If the stressor and GCs were released within the past few hours, the effects may be anti-inflammatory but at least at normal levels, if the stressor occurred in the prior day, the effects may actually be pro-inflammatory.
Michael Bailey was the recipient of the Robert Ader New investigator award and his presentation was entitled The intestinal microbiota are interactively involved in stressor-induced immunomodulation. Annemieke Kavelaars was the recipient of the Norman Cousins Award and her presentation was Neuro-immune communication: The target tissue decides. Other events of the day included a brief poster data blitz where select people with posters presented a couple slides previewing their results as well as a poster session.