Hoyer, Friedrich F - CAP 22

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.

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.

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.

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.