Contribution of Extramedullary Hematopoiesis to Atherosclerosis. The Spleen as a Neglected Hub of Inflammatory Cells

Abstract

Cardiovascular diseases (CVDs) incidence is becoming higher. This fact is promoted by metabolic disorders such as obesity, and aging. Atherosclerosis is the underlying cause of most of these pathologies. It is a chronic inflammatory disease that begins with the progressive accumulation of lipids and fibrotic materials in the blood-vessel wall, which leads to massive leukocyte recruitment. Rupture of the fibrous cap of the atherogenic cusps is responsible for tissue ischemic events, among them myocardial infarction. Extramedullary hematopoiesis (EMH), or blood cell production outside the bone marrow (BM), occurs when the normal production of these cells is impaired (chronic hematological and genetic disorders, leukemia, etc.) or is altered by metabolic disorders, such as hypercholesterolemia, or after myocardial infarction. Recent studies indicate that the main EMH tissues (spleen, liver, adipose and lymph nodes) complement the hematopoietic function of the BM, producing circulating inflammatory cells that infiltrate into the atheroma. Indeed, the spleen, which is a secondary lymphopoietic organ with high metabolic activity, contains a reservoir of myeloid progenitors and monocytes, constituting an important source of inflammatory cells to the atherosclerotic lesion. Furthermore, the spleen also plays an important role in lipid homeostasis and immunecell selection. Interestingly, clinical evidence from splenectomized subjects shows that they are more susceptible to developing pathologies, such as dyslipidemia and atherosclerosis due to the loss of immune selection. Although CVDs represent the leading cause of death worldwide, the mechanisms involving the spleenatherosclerosis-heart axis cross-talk remain poorly characterized.

Extramedullary Hematopoiesis of the Liver and Spleen

“…The sensitivity of asplenic or splenectomized mice to massive bacterial infections is caused by the lack of IgM memory B cells [21]. The spleen is regarded as the main site of EMH in different hematopoietic disorders: primary myelofibrosis (PMF) [22,23], acute myeloid leukemia (AML), hemolytic anemia, thalassemia, non-Hodgkin's lymphoma (NHL), immune thrombocytopenic purpura (ITP) [24], as well as spondylarthritis [25], atherosclerosis [26], and osteopetrosis (marble bone disease) [8]. The numerous splenic EMH diseases sustain the conclusion that the spleen is the main EMH site, but it is functionally and mechanistically different from the BM regarding blood cell formation [9].…”

NOD1-Targeted Immunonutrition Approaches: On the Way from Disease to Health

“…The immune system is a highly complex defense network of mechanisms, signals, cells, organs, and tissues, whose goal is to protect the human being. Conventional versus nonconventional or extramedullary hematopoiesis are key processes by which blood cellular components (including the most relevant immune actors, leukocytes) are formed [ 19 ]. However, this intricate system is extremely variable between subjects and can also cause illness when it fails or there are deficiencies in its performance.…”

Myelopoiesis during Solid Cancers and Strategies for Immunotherapy

“…Extramedullary hematopoiesis (EMH), when hematopoiesis occurs outside of the bone marrow niche, is well characterized in embryonic development. However, EMH can also occur under inflammatory conditions such as atherosclerosis [ 54 ], sepsis [ 55 ], and infection [ 56 ]. Clinically, the most common sites of extramedullary hematopoiesis are the spleen and liver.…”