Thrombospondin-1: an extracellular message delivered by macrophages that promotes aortic aneurysms.

Abstract

Inflammation plays a critical role in a broad range of human diseases. The immune system must create sufficient inflammation to protect the host from infectious agents without causing hypercytokinemia and chronic inflammation that increases the risk for developing diseases ranging from autoimmunity to cancer. Many factors influence the strength and duration of inflammatory responses, including genetics, environmental factors, and the microbiome.1 Recruitment of circulating innate immune cells is a key step in initiating local inflammation, and the work of Liu et al2 in this issue provides novel insights into the role of bone marrow (BM)–derived inflammatory cells in the pathogenesis of abdominal aortic aneurysms (AAA). Article, see p 129 The pathogenesis of human AAA occurs over many years and involves decreased elastin deposition, increased vascular smooth muscle cell death, immune cell infiltration, atherosclerosis, and thrombi. In contrast, mouse models of AAA use an acute injury to generate chronic aortic inflammation, leading to aneurysm formation in the following weeks.3 The elastase and CaCl2 models induce pathologies that resemble human AAA and are the preferred models to address the role of inflammatory cells and study specific gene deletions. The angiotensin-II model is restricted to Apoe −/− mice but exhibits robust thrombus and atherosclerosis pathology that is lacking from other models. Liu et al2 identify an important role for BM-derived monocytes and thrombospondin-1 in each of these models and in human AAA tissues. The authors had several reasons to focus on the secreted matricellular protein thrombospondin-1. Thrombospondin-1 plays known roles in other diseases of large vessels, including atherosclerosis and pulmonary arterial hypertension,4 and signaling through thrombospondin-1 receptors on vascular cells controls signaling pathways that regulate vascular physiology.5 Thrombospondin-1 is also known to regulate inflammatory responses in infectious diseases, cardiovascular disease, reperfusion injuries, and cancer.6– …