Claudio Vinegoni, Ph.D. | Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease

Nature
Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease

McAlpine, C. S., Park, J., Griciuc, A., Kim, E., Choi, S. H., Iwamoto, Y., Kiss, M. G., Christie, K. A., Vinegoni, C., Poller, W. C., Mindur, J. E., Chan, C. T., He, S., Janssen, H., Wong, L. P., Downey, J., Singh, S., Anzai, A., Kahles, F., Jorfi, M., Feruglio, P. F., Sadreyev, R. I., Weissleder, R., Kleinstiver, B. P., Nahrendorf, M., Tanzi, R. E., and Swirski^#, F. K.

Nature 2021

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Communication within the glial cell ecosystem is essential for neuronal and brain health(1-3). The influence of glial cells on the accumulation and clearance of beta-amyloid (A beta) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions(4,5). Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of A beta deposits, microglia increase their expression of IL-3R alpha-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of A beta and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.
@article{2021-NATURE, author= {McAlpine, C. S. and Park, J. and Griciuc, A. and Kim, E. and Choi, S. H. and Iwamoto, Y. and Kiss, M. G. and Christie, K. A. and Vinegoni, C. and Poller, W. C. and Mindur, J. E. and Chan, C. T. and He, S. and Janssen, H. and Wong, L. P. and Downey, J. and Singh, S. and Anzai, A. and Kahles, F. and Jorfi, M. and Feruglio, P. F. and Sadreyev, R. I. and Weissleder, R. and Kleinstiver, B. P. and Nahrendorf, M. and Tanzi, R. E. and Swirski<sup>#</sup>, F. K.}, title= {Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease}, journal= {Nature}, alternatejournal = {Nature}, year = {2021}, volume = {595}, number = {7869}, pages = {701-+}, issn = {0028-0836}, doi = {10.1038/s41586-021-03734-6}, pmcid = {PMC8934148}, pmid= {34262178} }
34262178

PMC8934148

10.1038/s41586-021-03734-6

Abstract

"Communication within the glial cell ecosystem is essential for neuronal and brain health(1-3). The influence of glial cells on the accumulation and clearance of beta-amyloid (A beta) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions(4,5). Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of A beta deposits, microglia increase their expression of IL-3R alpha-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of A beta and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD."

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McAlpine, C. S., Park, J., Griciuc, A., Kim, E., Choi, S. H., Iwamoto, Y., Kiss, M. G., Christie, K. A., Vinegoni, C., Poller, W. C., Mindur, J. E., Chan, C. T., He, S., Janssen, H., Wong, L. P., Downey, J., Singh, S., Anzai, A., Kahles, F., … Swirski^#, F. K. (2021). Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease. Nature, 595(7869), 701-+. https://doi.org/10.1038/s41586-021-03734-6