The role of Interleukin-3 in autoimmune myocarditis
Final Report Abstract
The aim of original proposal was to investigate the role interleukin-3 in autoimmune myocarditis. Preliminary data for this project had already been established and significantly advanced at the start of the fellowship. In the light of this and the fact that the influence of lifestyle factors, such as sleep, stress and diet on cardiovascular health and response to infection had become a major focus of the laboratory, the main project shifted to the aim of investigating how fasting changes hematopoiesis and the leukocyte landscape throughout the organism. Diet profoundly influences physiology. Whereas over-nutrition elevates risk for disease via its influence on immunity and metabolism, caloric restriction and fasting appear to offer health benefits. Despite multiple correlations observed between diet and health, the underlying cellular and molecular biology remains largely unknown. In this project, we identified a fasting-induced directional switch in leukocytes’ migration behavior that prolongs monocyte lifespan and alters disease susceptibility in mice. We showed that fasting during the active phase of the circadian period (dark period of the day) induces rapid return of monocytes from the periphery to the bone marrow. This monocyte re-entry to the bone marrow was orchestrated by a brain-body circuit involving the upregulation of the major leukocyte homing factor CXCR4 via the hypothalamic-pituitary-adrenal (HPA)-axis. Though the marrow is a safe haven for sequestered monocytes during nutrient scarcity, re-feeding after fasting prompted a mobilization event, resulting in monocytosis of chronologically older and transcriptionally distinct monocytes. These fasting-induced shifts impaired the animal’s response to infection. Our study showed that diet—and in particular a diet’s temporal dynamic balance—modulates monocyte lifespan, with consequences on adaptation to external stressors.
Publications
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Liver X receptors are required for thymic resilience and T cell output, Exp Med 2020 Oct 5;217(10):e20200318
Christopher T Chan, Ashley M Fenn, Nina K Harder, John E Mindur, Cameron S McAlpine, Jyoti Patel, Colin Valet, Sara Rattik, Yoshiko Iwamoto, Shun He, Atsushi Anzai, Florian Kahles, Wolfram C Poller, Henrike Janssen, Lai Ping Wong, Carlos Fernandez-Hernando, David R Koolbergen, Anja M van der Laan, Laurent Yvan-Charvet, Ruslan I Sadreyev, Matthias Nahrendorf, Marit Westerterp, Alan R Tall, Jan-Ake Gustafsson, Filip K Swirski
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Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease, Nature 2021 Jul;595(7869):701-706
Cameron S McAlpine, Joseph Park, Ana Griciuc, Eunhee Kim, Se Hoon Choi, Yoshiko Iwamoto, Máté G Kiss, Kathleen A Christie, Claudio Vinegoni, Wolfram C Poller, John E Mindur, Christopher T Chan, Shun He, Henrike Janssen, Lai Ping Wong, Jeffrey Downey, Sumnima Singh, Atsushi Anzai, Florian Kahles, Mehdi Jorfi, Paolo Fumene Feruglio, Ruslan I Sadreyev, Ralph Weissleder, Benjamin P Kleinstiver, Matthias Nahrendorf, Rudolph E Tanzi, Filip K Swirski
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Brain motor and fear circuits regulate leukocytes during acute stress, Nature 2022 Jul;607(7919):578-584
Wolfram C Poller, Jeffrey Downey, Agnes A Mooslechner, Nargis Khan, Long Li, Christopher T Chan, Cameron S McAlpine, Chunliang Xu, Florian Kahles, Shun He, Henrike Janssen, John E Mindur, Sumnima Singh, Máté G Kiss, Laura Alonso-Herranz, Yoshiko Iwamoto, Rainer H Kohler, Lai Ping Wong, Kashish Chetal, Scott J Russo, Ruslan I Sadreyev, Ralph Weissleder, Matthias Nahrendorf, Paul S Frenette, Maziar Divangahi, Filip K Swirski
