We take a multidisciplinary approach to investigate the immune system in sleep, cardiovascular disease, and neurodegenerative diseases.
Project 1. Sleep’s influence on cardiovascular disease
Sleep is critical to health, and we should be asleep for a third of our life. Despite its importance more than a third of adults do not get sufficient sleep. We study how sleep protects against cardiovascular disease and vascular inflammation. We have shown that sleep fragmentation activates hematopoiesis in the bone marrow leading to an oversupply of circulating immune cells, enlarging atherosclerotic lesions (Nature, 2019). We identified a neuro-immune axis linking the brain’s hypothalamus to the control of immune growth factors in the bone marrow. We have also shown that sleep mediates the epigenetic programming and heterogeneity of hematopoietic stem cells and alters the emergence of clonal hematopoiesis (Cell, 2021; JEM 2022). Moving forward, we are exploring the many complex pathways and systems that link sleep to immune cell biology and cardiovascular health.
Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis. Cell. 2021 Mar 4;184(5):1348-1361.e22. doi: 10.1016/j.cell.2021.01.049. Epub 2021 Feb 25.PMID: 3363612 *equal contribution
Sleep modulates haematopoiesis and protects against atherosclerosis. Nature. 2019 Feb;566(7744):383-387. doi: 10.1038/s41586-019-0948-2. Epub 2019 Feb 13. PMID: 30760925
Sleep exerts lasting effects on hematopoietic stem cell function and diversity. McAlpine C, Kiss M, Zuraikat F, Cheek D, Schiroli G, Amatullah H, Huynh P, Bhatti M, Wong LP, Yates A, Poller W, Mindur J, Chan C, Janssen H, Downey J, Singh S, Sadreyev R, Nahrendorf M, Jeffrey K, Scadden D, Naxerova K, St-Onge MP†, Swirski FK Journal of Experimental Medicine, 2022, 219(11)1-16
Project 2. Immune growth factors in neurodegenerative diseases
The immune system plays an important role in the pathophysiology of Alzheimer’s disease (AD). We pursue research exploring glial cell communication and the role of growth factors in mediating the biology of astrocytes and microglia in neurodegeneration. Interleukin-3 is a multifunctional cytokine and growth implicated in many inflammatory and autoimmune diseases. We have shown, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs IL-3RA-expressing microglia and other myeloid cells to generate immune recruitment and chemotactic programming. In the context of Alzheimer’s disease (AD) this is beneficent as IL-3 endows with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau, ameliorating AD (McAlpine et al. Nature 2021). In multiple sclerosis (MS) IL-3 stimulation of myeloid chemoattraction is detrimental and perpetuates neuroinflammation and the recruitment of immune cells to the CNS to worsen MS and it’s preclinical model EAE (Kiss et al. Immunity 2023). These data highlight the importance of balancing and fine-tuning inflammation in neurodegenerative diseases and position IL-3 as a critical player in neuroinflammatory balance that could be targeted to equilibrate immune responses in the brain.
Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease.Nature. 2021 Jul;595(7869):701-706. PMID: 34262178
Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis. Kiss M., Mindur J., Yates A., Lee D., Fullar J., Anzai A., Poller W., Christie K., Iwamoto Y., Roudko V., Downey J., Chan C., Huynh P., Janssen H., Ntranos A., Hoffmann J., Jacob W., Goswami S., Singh S., Leppert D., Kuhle J., Kim-Schulze S., Nahrendorf M., Kleinstiver B., Probert F., Roussos P., Swirski F., McAlpine C. Immunity, 2023. (56)1-13.