New research published today in Cell by IFM Therapeutics co-founder Dr. Eicke Latz has shown that an unhealthy Western diet triggers the NLRP3 inflammasome to activate the body’s immune system, much like the way it does when faced with a bacterial infection. Research showed that even after shifting back to a healthier diet, the body’s cells undergo epigenetic, transcriptional and functional reprogramming, both in the immune system and bone marrow that may have long-term consequences. IFM Therapeutics, LLC (IFM), a privately held biopharmaceutical company, will use these and other data from Dr. Latz to develop therapies that modulate the innate immune system to treat inflammatory disorders and cancer.
In this recent work, Latz’s team found that the NLRP3 inflammasome, which is an intra-cellular sensor for danger signals to alert the immune system to respond to threats in the body, mediates Western diet-induced systemic inflammation and myeloid precursor programming. These findings demonstrate new potential therapeutic opportunities to interfere with diet-associated pathologies, many of which are underlaid by inappropriate immune activation.
“It has only recently been discovered that the innate immune system has a memory,” explained Eicke Latz, M.D., Ph.D., IFM Co-Founder and Founder and Director of the Institute of Innate Immunity, University of Bonn, who spearheaded a multinational group of researchers for the study. “After an infection, the body’s defenses remain in a hyperactive, alarmed state, so that it can respond more quickly to a new attack. Our team of researchers discovered that the Western diet has a similar impact, and, therefore, these findings have enormous relevance to society and potential therapeutic implications.”
Western Diet as a Trigger of Inflammation and Induced Trained Immunity
Several studies have demonstrated that the Western diet (WD), characterized by an overconsumption of refined sugars, salt, and saturated fat, triggers sterile (or non-pathogenic) inflammation in the body, and can lead to a range of chronic illnesses including cardiovascular disease and atherosclerosis, type 2 diabetes and cancer.
In this study, researchers studied three groups of mice: a control group that was fed a standard chow diet (CD), a second group that was fed a Western diet, and a third group that was fed a Western diet and then subsequently changed to standard chow diet. The WD-fed mice consequently developed widespread inflammation throughout the body, as measured by an increased level of inflammation associated proteins. Mice fed the standard CD did not exhibit these signs of inflammation. Mice fed WD, then switched to CD, saw systemic signs of inflammation decrease when they transitioned away from WD. However, despite the reduction in systemic inflammation, immune cells within the bone marrow of these mice remained functionally altered, likely as a consequence of epigenetic reprogramming by the inflammatory WD.
Bone marrow cells and splenic macrophages from each group of mice were isolated and tested ex vivo. A panel of known innate immune triggers were screened against these cells and secretion of inflammatory proteins were analyzed as a measure of innate immune response. Cells isolated from WD-fed mice exhibited increased and altered responses to immune triggers, when compared to cells obtained from mice on CD. Interestingly, cells isolated from mice first fed WD and then transitioned to CD exhibited sustained altered responses to stimuli similar to that of exclusively WD-fed mice. These data indicate that even though systemic inflammation decreased when mice transitioned to CD after WD feeding, the bone marrow cells retained memory of the inflammation caused by WD. This research confirms that WD can produce not only an immediate innate immune response, but also drives a long-lasting impact by inducing an innate immune memory response.
Role of the NLRP3 Inflammasome in Trained Immunity
In order to elucidate the specific pathways associated with this type of inflammation, mice lacking the NLRP3 protein were fed similar dietary programs. Interestingly, mice lacking the NLRP3 protein did not produce similar inflammatory responses, nor did they have sustained inflammatory activity, suggesting that the NLRP3 protein plays a key role in WD-triggered innate immunity.
“The research published by Dr. Latz’s team shows the long-term damage that an unhealthy Western diet inflicts on the immune system, even after changing dietary habits,” said H. Martin Seidel, Ph.D., Executive Vice President of R&D at IFM Therapeutics. “Identifying the NRLP3 inflammasome as the trigger of lasting immune-cell changes and a hyper-activated inflammatory state opens a tremendous opportunity to develop potential therapies that inhibit NLRP3 activity, and as such, slow the development of cardiovascular and metabolic diseases, such as atherosclerosis and type 2 diabetes.”