The role of interleukin 3 in atherosclerosis
Final Report Abstract
This project evaluates the role of interleukin 3 (IL-3) in atherosclerosis. We hypothesized that IL- 3 accelerates inflammatory leukocyte production in the bone marrow and therefore promotes atherosclerotic plaque growth. Surprisingly, however, atherosclerotic mice that lack IL-3 develop larger plaques compared to control mice. As of today, in depth mechanistic studies involving bone marrow transplantation experiments, flow cytometry, gene expression profiling, and cellspecific knockout models suggest a mechanism, in which IL-3 produced by stromal cells in the plaque acts on plaque macrophages improving their capacity to perform functions such as efferocytosis. The time-consuming development of cell-specific knockout models on atherosclerotic background, involving CRISPR/Cas9 based generation of an entirely new mouse line as well as multiple breeding steps thereafter have significantly advanced this project and will allow us to answer the remaining questions in a timely manner. In the meantime, I developed a second main project that combined my backgrounds in neuroscience, cardiology, and immunology. The purpose of this project was to understand how different brain regions control the immune system under conditions of psychosocial stress. Using state-of-the-art tools of neuromodulation including chemo- and optogenetics alongside with classical immunological techniques, we precisely describe how specific brain regions induce large-scale leukocyte shifts between the bone marrow and peripheral organs within hours of stress exposure. During acute stress, high numbers of neutrophils are released from the bone marrow to prepare the body for potential injuries in fight or flight situations, whereas monocytes and lymphocytes show a mass migration into the bone marrow to potentially prevent the development of autoimmunity during episodes of tissue injury with high levels of free autoantigens. While these large-scale bidirectional leukocyte shifts may be beneficial in fight-orflight situations, we show that they can be detrimental when acute stress coincides with exposure to influenza and SARS-CoV-2. The results have broad implications for our understanding of brain-immune communication and have recently been published in several Nature articles with widespread attention from the scientific community as well as from mainstream media outlets.
Publications
- Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease. Nature. 2019;566(7742):115-119
He S, Kahles F, Rattik S, Nairz M, McAlpine CS, Anzai A, Selgrade D, Fenn AM, Chan CT, Mindur JE, Valet C, Poller WC, Halle L, Rotllan N, Iwamoto Y, Wojtkiewicz GR, Weissleder R, Libby P, Fernández-Hernando C, Drucker DJ, Nahrendorf M, Swirski FK
(See online at https://doi.org/10.1038/s41586-018-0849-9) - Sleep modulates haematopoiesis and protects against atherosclerosis. Nature. 2019;566(7744):383-387
McAlpine CS, Kiss MG, Rattik S, He S, Vassalli A, Valet C, Anzai A, Chan CT, Mindur JE, Kahles F, Poller WC, Frodermann V, Fenn AM, Gregory AF, Halle L, Iwamoto Y, Hoyer FF, Binder CJ, Libby P, Tafti M, Scammell TE, Nahrendorf M, Swirski FK
(See online at https://doi.org/10.1038/s41586-019-0948-2) - Hematopoiesis and Cardiovascular Disease. Circ Res. 2020;126(8):1061-1085
Poller WC, Nahrendorf M, Swirski FK
(See online at https://doi.org/10.1161/circresaha.120.315895) - Liver X receptors are required for thymic resilience and T cell output. J Exp Med. 2020;217(10):e20200318
Chan CT, Fenn AM, Harder NK, Mindur JE, McAlpine CS, Patel J, Valet C, Rattik S, Iwamoto Y, He S, Anzai A, Kahles F, Poller WC, Janssen H, Wong LP, Fernandez- Hernando C, Koolbergen DR, van der Laan AM, Yvan-Charvet L, Sadreyev RI, Nahrendorf M, Westerterp M, Tall AR, Gustafsson JA, Swirski FK
(See online at https://doi.org/10.1084/jem.20200318) - Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease. Nature. 2021 Jul;595(7869):701-706
McAlpine CS, Park J, Griciuc A, Kim E, Choi SH, Iwamoto Y, Kiss MG, Christie KA, Vinegoni C, Poller WC, Mindur JC, Chan CT, He S, Janssen H, Wong LP, Downey J, Singh S, Anzai A, Kahles F, Jorfi M, Feruglio PF, Sadreyev RI, Weissleder R, Kleinstiver BP, Nahrendorf M, Tanzi RE, Swirski FK
(See online at https://doi.org/10.1038/s41586-021-03734-6) - Brain motor and fear circuits regulate leukocytes during acute stress. Nature. 2022 Jul;607(7919):578-584
Poller WC, Downey J, Mooslechner AA, Khan N, Li L, Chan CT, McAlpine CS, Xu C, Kahles F, He S, Janssen H, Mindur JE, Singh S, Kiss MG, Alonso-Herranz L, Iwamoto Y, Kohler RH, Wong LP, Chetal K, Russo SJ, Sadreyev RI, Weissleder R, Nahrendorf M, Frenette PS, Divangahi M, Swirski FK
(See online at https://doi.org/10.1038/s41586-022-04890-z) - Sleep exerts lasting effects on hematopoietic stem cell function and diversity. J Exp Med. 2022 Nov 7;219(11):e20220081
McAlpine CS, Kiss MG, Zuraikat FM, Cheek D, Schiroli G, Amatullah H, Huynh P, Bhatti MZ, Wong LP, Yates AG, Poller WC, Mindur JE, Chan CT, Janssen H, Downey J, Singh S, Sadreyev RI, Nahrendorf M, Jeffrey KL, Scadden DT, Naxerova K, St-Onge MP, Swirski FK
(See online at https://doi.org/10.1084/jem.20220081)
