Invited Commentary

Abstract

In this study by Deng and colleagues [1Deng X.-S. Meng X. Zeng Q.C. Fullerton D. Mitchell M. Jaggers J. Adult aortic valve interstitial cells have greater responses to Toll-like receptor 4 stimulation.Ann Thorac Surg. 2015; 99: 62-71Abstract Full Text Full Text PDF Scopus (8) Google Scholar], age-dependent differences in toll-like receptor-4 (TLR4) response to stimulation with lipopolysaccharide (LPS) were examined in pediatric and adult aortic valve interstitial cells (AVICs) in an effort to identify underlying mechanisms that contribute to the pathogenesis of calcific aortic valve disease. The AVIC is the principal cell type in the aortic valve leaflet and has been implicated in the disease process by undergoing phenotypic changes that result in the activation of proinflammatory and proosteogenic responses that activate bone-formation signaling pathways and ultimately result in stiffening of valve leaflets. The key findings of this study demonstrated that the p38 mitogen activated protein kinase (p38MAPK) and nuclear factor-κ B (NFκB) inflammatory pathways were elevated in adult AVICs in response to LPS but not in pediatric AVICs. This was associated with an increase in protein levels of proosteogenic mediators intercellular adhesion molecule 1 (ICAM-1), bone morphogenetic protein-2 (BMP-2), and alkaline phosphatase (ALP). Importantly, the authors demonstrated that the difference in age-dependent response to LPS was not due to changes in TLR4 protein levels (the primary cellular receptor for LPS) but to the loss of tyrosine phosphorylation of signal transducer and activator of transcription-3 (STAT3). This was further supported by elegant work showing that the inhibition of STAT3 in young AVICs, by use of either a pharmacologic STAT3 inhibitor or a short-hairpin ribonucleic acid designed to suppress STAT3 translation, could mimic the LPS response of adult AVICs. Together, these studies suggest that age-dependent differences in TLR4 signaling alter the response of adult AVICs to inflammatory stimuli, and they implicate the loss of STAT3 activation as one mechanism that may contribute to the pathogenesis of calcific aortic valve disease. The authors speculate that the inhibition of TLR4 activation may show a clinical benefit. However, while there has been ongoing interest in the identification of small molecule inhibitors of TLR4, only a limited number of candidate drugs have made it into clinical trials, highlighting the difficulty of targeting a key component of the innate immune system. Further elucidation of the signaling pathways leading to STAT3 activation in pediatric AVICs may help identify the age-dependent defects in STAT3 activation and may identify alternative mechanisms that could be targeted for therapeutic advantage. For example, targeting the activation of AVICs through the inhibition of pathways that mediate cellular phenotype change, such as BMP-2, may attenuate the pathologic responses to TLR4 stimulation in adult cells. This is a very interesting and thought-provoking area of study, and Deng and colleagues should be congratulated for their excellent work. Adult Aortic Valve Interstitial Cells Have Greater Responses to Toll-Like Receptor 4 StimulationThe Annals of Thoracic SurgeryVol. 99Issue 1PreviewAortic valve interstitial cells (AVICs) have been implicated in the pathogenesis of calcific aortic valve disease. Signal transducer and activator of transcription 3 (Stat3) possesses antiinflammatory effects. Given that calcification occurs in adult valves, we hypothesized that AVICs from adult valves more likely undergo a proosteogenic phenotypic change than those from pediatric valves and that may be related to different Stat3 activation in the response of those two age groups to toll-like receptor 4 (TLR4). Full-Text PDF