Ying and Yang of Stat3 in pathogenesis of aortic dissection

Abstract

Aortic dissection (AD) is a medical emergency, in which acute destruction of aortic wall occurs with unknown etiology. Recent studies have uncovered the critical role of inteleukin-6 (IL-6) and inflammatory cells including macrophages in the disease mechanism of AD. IL-6 activates janus kinase and signal transducer and activator of transcription 3 (STAT3) to alter the gene expression program in many cell types, thus regulating various aspects of inflammatory response. We found that in human AD tissue, STAT3 was activated in infiltrating macrophages and in medial smooth muscle cells (SMCs), suggesting that STAT3 may regulate the response of these cell types. However, it is unknown how Stat3 regulates the cell type-specific response in pathogenesis of AD. The role of STAT3 was examined in genetically modified mice in which STAT3 sensitivity was enhanced specifically in macrophages or in SMCs by tissue-specific deletion of suppressor of cytokine signaling 3 (Socs3), a negative regulator of STAT3. Macrophage-specific deletion of Socs3 caused acute enhancement of STAT3 activation, M1-dominant differentiation of macrophages, suppression of tissue repair response of SMCs, and exaggerated AD. In contrast, SMC-specific deletion of Socs3 caused chronic STAT3 activation and low-grade inflammatory response in aortic walls, activation of fibroblasts, M2-dominant differentiation of macrophages, increase in adventitial collagen deposition, resulting in the protection of aorta from AD by reinforcing the tensile strength of the aortic walls. Therefore, STAT3 regulates the balance between the destruction and the reinforcement of the aortic tissue, depending on the cell types and the time course of STAT3 activation, which ultimately regulates the development of AD. Elucidating such a dynamic mechanism to regulate the aortic tissue integrity would be essential to decipher the molecular pathogenesis of AD.

Keywords: Aortic dissection; Macrophage; Molecular pathogenesis; Signal transducer and activator of transcription 3; Smooth muscle cells.