The Nahrendorf laboratory focuses on the role of immunity in cardiovascular health and disease, specifically in atherosclerosis and heart failure. Of particular interest are the function, supply and production of leukocytes, and the signals that regulate hematopoiesis after injuries such as myocardial infarction or stroke. We described that after MI, the spleen releases a large population of ready-made leukocytes that travel to the ischemic heart (Science 2009, New York Times 2009). We further found that MI, chronic stress and sedentary life style modulate the hematopoietic stem cell niche, activating migration and proliferation of myeloid progenitor cells (Nature 2012, Nature Med 2014, Nature Med 2019). Resident macrophages, on the other hand, do not derive from circulating cells and promote steady state functions such as cardiac conduction (Cell 2017). The laboratory also develops and employs imaging to sample biology non-invasively, using MR, nuclear, optical and microscopic modalities.
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 Brain motor and fear circuits regulate leukocytes during acute stress. Nature. 2022;:ePub - PMID: 35636458 - DOI: 10.1038/s41586-022-04890-z
Pulous FE, Cruz-Hernandez JC, Yang C, Kaya Z, Paccalet A, Wojtkiewicz G, Capen D, Brown D, Wu JW, Schloss MJ, Vinegoni C, Richter D, Yamazoe M, Hulsmans M, Momin N, Grune J, Rohde D, McAlpine CS, Panizzi P, Weissleder R, Kim DE, Swirski FK, Lin CP, Moskowitz MA, Nahrendorf M Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis. Nat Neurosci. 2022;25(5):567-576 - PMID: 35501382 - PMCID: PMC9081225 - DOI: 10.1038/s41593-022-01060-2
Schloss MJ, Hulsmans M, Rohde D, Lee IH, Severe N, Foy BH, Pulous FE, Zhang S, Kokkaliaris KD, Frodermann V, Courties G, Yang C, Iwamoto Y, Knudsen AS, McAlpine CS, Yamazoe M, Schmidt SP, Wojtkiewicz GR, Masson GS, Gustafsson K, Capen D, Brown D, Higgins JM, Scadden DT, Libby P, Swirski FK, Naxerova K, Nahrendorf M B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis. Nat Immunol. 2022;23(4):605-618 - PMID: 35352063 - PMCID: PMC8989652 - DOI: 10.1038/s41590-022-01165-7
Rohde D, Vandoorne K, Lee IH, Grune J, Zhang S, McAlpine CS, Schloss MJ, Nayar R, Courties G, Frodermann F, Wojtkiewicz G, Honold L, Chen Q, Schmidt S, Iwamoto Y, Sun Y, Cremer S, Hoyer FF, Iborra-Egea O, Muñoz-Guijosa C, Fei Ji F, Zhou B, Adams RH, Wythe JD, Hidalgo J, Watanabe H, Jung Y, van der Laan AM, Piek JJ, Kfoury Y, Désogère PA, Vinegoni C, Dutta P, Sadreyev RI, Caravan P, Bayes-Genis A, Libby P, Scadden DT, Lin CP Naxerova K, Swirski FK, Nahrendorf M Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease. Nat Cardiovasc Res. 2022;1:28–44 - PMID: 35747128 - PMCID: PMC9216333 - DOI: 10.1038/s44161-021-00002-8
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Leukocytes in cardiovascular health
The Nahrendorf laboratory shares a longstanding interest with the Swirski lab in innate immune cells, especially myeloid cells. We discovered that healing after myocardial infarction involves time-resolved monocyte and macrophage subset dynamics. We identified a splenic monocyte reservoir, which deploys within 24 hours after myocardial infarction. This reservoir contributes half of all monocytes recruited to the infarct. In atherosclerosis and chronic heart failure, macrophages expand by proliferating locally, and there is interaction between local and systemic inflammation, including in the remote myocardium after ischemic injury. In the healthy heart, cardiac resident macrophages connect to myocytes via gap junctions and participate in electric conduction; their depletion leads to conduction abnormalities such as AV block.
Activation of hematopoiesis in cardiovascular disease
We described the mechanisms behind acceleration of atherosclerotic disease after a first infarct in the heart or brain. Infarct-induced sympathetic nervous system signaling in the bone marrow activates hematopoietic stem cells, which begin to proliferate and relocate to the spleen where they over-produce leukocytes. The most upstream point of hematopoiesis activation rests in CCR2+ hematopoietic stem cells. Newly produced leukocytes migrate to the atherosclerotic plaque, rendering it more inflamed and vulnerable to rupture, triggering reinfarction, a frequent clinical event that was previously unexplained. The findings are clinically important as they provide a new therapeutic opportunity to prevent secondary complications of atherosclerosis. We subsequently observed similar pathway activation after ischemic stroke and during exposure to chronic psychosocial stress.
In vivo RNAi for immunomodulation
In collaboration with MIT and Alnylam, we pioneered in vivo RNAi to silence the chemokine receptor CCR2, and subsequently other targets, in monocytes, macrophages and endothelial cells. Delivered by nanoparticles, siRNA is incorporated into splenic and circulating monocytes and macrophages, resulting in efficient silencing of gene expression. These cells 'lose their GPS', i.e. they are no longer able to migrate to the site of inflammation. This new class of anti-inflammatory therapy is highly selective, as it only targets certain genes. Subsequently we have targeted other proteins in myeloid cells and their progenitors as well as endothelial cells.