On 19 March 2018, eleven researchers received the DFG's (German Research Foundation's) Leibniz Prize. One of them is Prof. Eicke Latz, Director of the Institute of Innate Immunity at the University of Bonn and a DZNE researcher. The Leibniz Prize is Germany’s most prestigious research funding prize. Latz is receiving the prize, which includes prize money of 2.5 million euros, along with Veit Hornung, a research colleague based at LMU Munich with whom Latz has collaborated extensively. The two men are seen as two of the world's leading researchers in the field of innate immunity.
The innate immune system provides the body's first rapid immune responses to pathogenetic microorganisms. It can also be activated by sterile inflammation related to tissue injury. The cells of the innate immune system recognize and attack microbes, and they emit messenger substances that activate other parts of the immune system that are able to react specifically to certain pathogens. In addition, the same cells can also initiate repair processes following tissue injury.
The immune system protects the body against infectious diseases. While this role is crucially important, a heightened immune response can also have negative consequences. Pathogens are not the only factor that can activate the immune system and trigger inflammation. Changes in tissues can also do these things. As people age, such changes tend to become more and more common, and the resulting immune reactions can lead to diseases such as arteriosclerosis, cancer, Alzheimer's and Parkinson's disease.
Prof. Latz, your research focuses on the innate immune system. What do you find fascinating about that immune system?
In the last two decades, we have learned a great deal about the molecular mechanisms underlying activation of the innate immune system, and we have realized that misdirected activation of the innate immune system contributes to the pathogenesis of many common diseases. Researchers working in this area have thus been able to identify many pharmacological target molecules that can now serve as the focus of new, more-specific medications for modulating the body's immune response. While the innate immune system can be activated by bacteria and viruses, it can also be activated by endogenous substances that occur in various metabolic disorders and that can accumulate and precipitate, especially as we age. In many of today's widespread diseases, an overreaction of the immune system takes place, due to the presence of certain endogenous substances, and the resulting misdirected inflammatory response becomes part of the disease process. A broad field for new therapeutic strategies thus awaits.
An important part of your research focuses on the NLRP3 inflammasome. What is that?
The NLRP3 inflammasome is an important receptor of the innate immune system that regulates the activation of messenger substances that are particularly inflammatory. The NLRP3 inflammasome is seen especially as a maintainer of non-infectious inflammatory processes. It responds to a wide range of different endogenous substances, such as aggregated or crystalline metabolic products, as well as to a number of aggregates that play an important role in neurodegenerative processes, such as brain plaques tied to Alzheimer's or Parkinson's.
So Alzheimer's triggers an inflammation. Is that simply a side effect of the disease, or is it a factor that keeps the disease moving forward?
Opinions differ on this point. Personally, I think that neurodegeneration and inflammatory processes are mutually reinforcing. In a study carried out in collaboration with Michael Heneka, we have shown, in an Alzheimer's mouse model, that NLRP3 triggers an inflammatory response. Mice that lack the NLRP3 inflammasome do not exhibit the typical symptoms of Alzheimer's disease in this model and do not suffer memory loss for example.
In another study, which we published last year, we showed that the immune system and neurodegeneration can become linked in a sort of vicious circle. Amyloid-beta aggregates – characteristic deposits found in the brains of Alzheimer's patients – can activate the inflammasome. When that happens, cells release part of the inflammasome, and this, in turn, promotes amyloid-beta aggregation. This discovery provided a first indication of how the inflammatory response could be directly hard-wired to neurodegeneration. The results also suggest that inflammasomes could potentially be target molecules for new types of Alzheimer's therapies.
In a more recent study, you have shown that a poor diet can overstimulate the immune system. What role does diet play in neurodegenerative diseases?
That role is not yet fully understood, and it is the focus of our current work. For some time now, it has been known that overweightness in middle age is a risk factor for neurodegenerative diseases. In this current study that you refer to, we show that the so-called "Western" diet, i.e. a diet rich in fats, suger, salt and calories, can make the body's immune defenses more aggressive in the long term. We show that such unhealthy eating habits can activate the NLRP3 inflammasome, and thereby trigger a systemic inflammation, just as an infectious disease would.
In addition, we have found that such chronic inflammatory responses sensitize the immune system, with the result that it then responds more viciously to other substances or to tissue injury. Consequently, an unhealthy diet is very closely tied, mechanistically, to the root causes of widespread modern-day diseases. Additionally, the pertinent changes get epigenetically stored, which means that an unhealthy diet can change the activatability of the immune system's cells in a lasting way or in other words, there is an innate immune memory of the inflammatory effects of Western diet.
Everybody knows that fast food is unhealthy, but nobody really knows exactly why. In this study, we wanted to produce firm data that would highlight the consequences of an unhealthy diet. By making relatively simple lifestyle changes – such as increasing exercise and improving diet – people can significantly reduce their risks of contracting today's major common diseases.
I think that the time has come to translate such results from basic research into new types of active substances. To this end, in 2016 I co-founded the start-up company IFM Therapeutics, which specializes in the development of modulators of the innate immune system. In addition, we aim to help raise awareness about the risks that can increase the likelihood of contracting chronic inflammatory diseases. Our research can help people better understand the risks involved in unhealthy nutrition habits. Our task now is to go out and present our work to the general public.
Text: Dr. Katrin Weigmann