Center for Molecular Medicine Cologne

Hoyer, Friedrich F - CAP 22

Myeloid Leukocytes in Cardiovascular and Systemic Inflammation

Introduction

The innate immune system crucially influences cardiovascular disease development and progression. Vascular inflammation, the underlying cause of atherosclerosis, engages circulating and vessel-resident leukocytes. Likewise, reperfusion following myocardial ischemia injures parenchymal and stromal cells, an effect significantly relayed by leukocytes. The myeloid leukocyte lineage consists of circulating subtypes such as monocytes and neutrophilic granulocytes. Neutrophils are shorter-lived, more abundant than monocytes, and reach sites of injury quickly. Like neutrophils, monocytes are constantly replenished by the marrow’s hematopoietic stem and progenitor cell population. They enter nascent atherosclerotic lesions early and relevantly influence the outcome after myocardial ischemic injury. Next to the circulating pool, tissue-resident macrophages are myeloid cells. They abound in most organs in the steady state and execute essential maintenance tasks. Their phenotypes significantly change in response to local or remote inflammation. While the CANTOS and COLCOT trials have proven the concept and feasibility in the clinical setting, immunomodulatory therapies are not yet available for the daily treatment of patients with cardiovascular disease. A more refined understanding of the underlying myeloid leukocyte biology will help fill this gap in the future and facilitate developing disease-specific treatment options.

    Research Activities

    Dr. Hoyer’s research focuses on mechanisms regulating the supply of inflammatory myeloid cells in acute and chronic inflammatory conditions. In this context, Dr. Hoyer examined how cardiovascular risk factors, such as hyperglycemia or hypercholesterolemia, influence myeloid leukocyte production in the bone marrow or spleen. For instance, Hoyer et al. observed that hyperglycemia profoundly elevates blood levels of circulating myeloid cells such as monocytes and granulocytic neutrophils in various diabetic models. Hematopoietic stem and progenitor cell numbers, which replenish the blood leukocyte’s pool in the steady state and during inflammation, increased numerically and displayed heightened proliferative activity. Distinct pathways in bone marrow niche cells kept excessive myeloid leukocyte production at bay. Disrupting the underlying signaling altered myeloid cell production and impacted downstream pathologies, such as atherosclerosis.

    Next to the myeloid cells’ supply chain, Dr. Hoyer’s group investigates the role and function of tissue-resident macrophages in cardiovascular and systemic inflammatory conditions. For instance, Hoyer et al. profiled macrophages systems-wide after sterile and non-sterile remote injuries. Whereas macrophages’ microenvironment generally dictates response patterns, distinct phenotypic adaptations determine macrophages’ reactions to secondary immune challenges and thus impact complications. For example, myocardial infarction primes alveolar macrophages, which conveys protection against subsequent bacterial lung infection but may also inflict collateral tissue damage.

    Clinical relevance

    Despite significant medical advances in the last decades, cardiovascular diseases remain leading in mortality statistics worldwide. Therapies altering the immune system in cardiovascular disease have proven beneficial in large, randomized trials. Yet, no treatment options are established in the clinical routine. A more detailed and improved picture of the underlying cellular mechanisms may aid the development of novel treatment options.

    Our aims and further perspectives

    We aim to contribute to a better understanding of myeloid leukocyte biology in cardiovascular and systemic inflammation. In this context, we specifically explore mechanisms governing inflammatory myeloid cell production in cardiovascular disease. Curbing the excessive supply of inflammatory cells contingent on the underlying pathology is feasible, but translation into practice requires additional insights. We further seek to refine the understanding of myeloid effector cells in cardiovascular and systemic inflammation to impede disease progression and prevent the development of systemic complications.

    • Heyde A, Rohde D, McAlpine CS, Zhang S, Hoyer FF, Gerold JM, Cheek D, Iwamoto Y, Schloss MJ, Vandoorne K, Iborra-Egea O, Muñoz- Guijosa C, Bayes-Genis A, Reiter JG, Craig M, Swirski FK, Nahrendorf M, Nowak MA, Naxerova K. Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis. Cell. 2021 Mar 4;184(5):1348-1361.e22.
    • Hoyer FF, Zhang X, Coppin E, Vasamsetti SB, Modugu G, Schloss MJ, Rohde D, McAlpine CS, Iwamoto Y, Libby P, Naxerova K, Swirski FK, Dutta P, Nahrendorf M. Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes. Circulation. 2020 Jul 21;142(3):244-258.
    • Hoyer FF, Naxerova K, Schloss MJ, Hulsmans M, Nair AV, Dutta P, Calcagno DM, Herisson F, Anzai A, Sun Y, Wojtkiewicz G, Rohde D, Frodermann V, Vandoorne K, Courties G, Iwamoto Y, Garris CS, Williams DL, Breton S, Brown D, Whalen M, Libby P, Pittet MJ, King KR, Weissleder R, Swirski FK, Nahrendorf M. Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge. Immunity. 2019;51:899-914.e7.
    • Frodermann V, Rohde D, Courties G, Severe N, Schloss MJ, Amatullah H, McAlpine CS, Cremer S, Hoyer FF, Ji F, van Koeverden ID, Herisson F, Honold L, Masson GS, Zhang S, Grune J, Iwamoto Y, Schmidt SP, Wojtkiewicz GR, Lee IH, Gustafsson K, Pasterkamp G, de Jager SCA, Sadreyev RI, MacFadyen J, Libby P, Ridker P, Scadden DT, Naxerova K, Jeffrey KL, Swirski FK, Nahrendorf M. Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells. Nat Med. 2019 Nov 7. doi: 10.1038/s41591-019-0633-x.
    • 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. Sleep modulates haematopoiesis and protects against atherosclerosis. Nature. 2019;566:383-387.
    • Hoyer FF, Nahrendorf M. Uremic Toxins Activate Macrophages. Circulation. 2019;139:97-100.
    • Hoyer FF, Nahrendorf M. Neutrophil contributions to ischaemic heart disease. Eur Heart J. 2017;38:465-472.
    • Dutta P, Hoyer FF, Grigoryeva LS, Sager HB, Leuschner F, Courties G, Borodovsky A, Novobrantseva T, Ruda VM, Fitzgerald K, Iwamoto Y, Wojtkiewicz G, Sun Y, Da Silva N, Libby P, Anderson DG, Swirski FK, Weissleder R, Nahrendorf M. Macrophages retain hematopoietic stem cells in the spleen via VCAM-1. J Exp Med.2015 April 6;212(4):497-512. PMID: 25800955.
    PD Dr. Friedrich Felix Hoyer CMMC Cologne
    PD Dr. Friedrich Felix Hoyer

    Clinic III of Internal Medicine

    CMMC - PI - CAP 22

    +49 221 478 36988

    Clinic III of Internal Medicine

    Kerpener Str. 62

    50937 Köln

    Publications - Friedrich F Hoyer

    Link to PubMed

    Group Members

    Simon Geißen, MD, PostDoc
    Alexander Hof, MD, PostDoc
    Charlotte Schreiber, MD student
    Kezia Singgih, MD student
    Jana Niehues, PhD student