Netrin-1 in obesity-associated inflammation and metabolic dysfunction
Final Report Abstract
Obesity and cardiovascular diseases have dramatically increased over the past decades and are major threats to global health. Chronic inflammation is mediated by accumulation and retention of proinflammatory monocytes in the adipose tissue and the arterial wall respectively. As is has been reported that the neuronal guidance protein netrin-1 plays a pivo tal role in the retention of macrophages, the progression of atherosclerosis and obesity induced inflammation, we tested how netrin-1 promotes the resolution of chronic inflammation and alters its local immune landscape. As both atherosclerosis and obesity are macrophage-driven, we developed a mouse model, in which macrophage-specific netrin-1 expression could be inducible deleted in obesity and atherosclerosis. The macrophage-specific loss of netrin-1 in obesity partly protected mice from diet-induced obesity and metabolic dysfunction. Ntn1deltaMo mice fed a high-fat diet changed the fate of the macrophages in the adipose tissue, licensing local adipose tissue macrophages to become less inflammatory and more regenerative. As a result Ntn1deltaMo mice gained less weight, less fat mass and showed overall a significantly improved metabolic function. To study the role of netrin-1 on atherosclerotic plaque regression, netrin-1 we deleted from mice that had already developed atherosclerotic plaques. The induced Mo-specific deletion of netrin-1 and its receptor Unc5b in established atherosclerosis decreases the local and systemic inflammation, and promoted the differentiation of proresolving macrophages. The reshaping of the plaque’s immune cell landscape, induced by deletion of netrin-1, led to a reduced plaque size in atherosclerotic mice and was therefore able to regress already established plaques. Targeting netrin-1 in atherosclerosis and in obesity is a therapeutic option to change the course of the disease and to regress impairments. However, in acute inflammation netrin-1 protects from an overwhelming inflammatory response and promotes tissue healing. Therefore, to provide a safe therapeutic option, it remains a major challenge for the field to understand the differences between acute and chronic inflammation and the conditions, under which the deletion of netrin-1 is beneficial and when it is detrimental.
Publications
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Connecting transcriptional and functional macrophage heterogeneity in atherosclerosis. Circulation Research, Vol. 125. 2019, No. 12, pp. 1052-1054.
Schlegel, M., Koelwyn, G.J., Moore, K.J.
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Netrin-1 Alters Adipose Tissue Macrophage Fate and Function in Obesity.
Immunometabolism, Vol.1. 2019, Issue 2: e190010.
Sharma, M., Schlegel M., Brown E.J., Sansbury B.E., Weinstock A., Afonso M.S., et al.
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Platelet Regulation of Myeloid Suppressor of Cytokine Signaling 3 Accelerates Atherosclerosis. Science Translational Medicine, Vol 11. 2019, Issue 517, eaax0481.
Barrett, T. J., M. Schlegel, F. Zhou, M. Gorenchtein, J. Bolstorff, K. J. Moore, E. A. Fisher, J. S. Berger
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A Heritable Netrin-1 Mutation Increases Atherogenic Immune Responses.
Atherosclerosis, Vol. 301. 2020, pp. 82-83.
Schlegel, M., K. J. Moore.
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Myocardial Infarction Accelerates Breast Cancer Via Innate Immune Reprogramming. Nature Medicine, Vol. 26. 2020, pp. 1452–1458.
Graeme J. Koelwyn, Alexandra A. C. Newman, Milessa S. Afonso, Coen van Solingen, Emma M. Corr, Emily J. Brown, Kathleen B. Albers, et al.
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Mir-33 Silencing Reprograms the Immune Cell Landscape in
Atherosclerotic Plaques. Circulation Research, Vol. 128. 2021, No. 8, pp. 1122–1138.
Afonso, M. S., M. Sharma, M. P. Schlegel, C. van Solingen, G. J. Koelwyn, L. C. Shanley, L., Beckett, et al.
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Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression. Circulation Research, Vol. 129. 2021, No. 5, pp. 530–546.
Schlegel, M. P., M. Sharma, E. J. Brown, A. A. Newman, Y. Cyr, M. S. Afonso, E. M. Corr, et al.
