Letter by Wang et al Regarding Article, “Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction”

September 1, 2020 e123 *Drs D. Wang, T. Wang, and Yang contributed equally. Daxin Wang, MD* Ti Wang, MD* Xinquan Yang, MD* To the Editor: We read with interest the article by Sreejit et al1 deciphering the proinflammatory effect of cardiac neutrophil-derived S100A8/A9 heterodimers through priming the nod-like receptor family pyrin domain-containing 3 inflammasome and then promoting interleukin-1β secretion on the amplification of granulopoiesis in bone marrow and deterioration of cardiac function after myocardial infarction (MI). However, calcium-induced S100A8/S100A9 tetramer hiding the TLR4 (Toll-like receptor 4)/ MD2 (myeloid differentiation factor 2) binding site displays an autoinhibitory regulation of locally restricted inflammatory activity of S100A8/S100A9 heterodimers, avoiding systemic side effects, and the involvement of S100A9 homodimers in improving metabolic imbalance and extending lifespan by TLR4 in insulin deficiency has been reported to limit the therapeutic effects of targeting S100A8/A9 signaling.2,3 These clues seem to imply that the functional variability of S100A8 and S100A9 is dependent on both their expression levels and different complex forms, which might be caused by the phenotypic heterogeneity and functional plasticity of bone marrow–derived neutrophils mobilized to heart during the different stages of acute inflammatory response after MI, and even lead to the contradiction of therapeutic strategies especially in patients with concomitant diseases such as autoimmune diseases or diabetes mellitus. Other S100 protein family members also have been indicated to be associated with the pathogenesis of acute coronary syndrome. Under myocardial ischemic injury or necrosis, for example, elevated serum levels and myocardial expression of S100B, S100A6, and S100P–mediated proinflammatory circle by S100–receptor for advanced glycation end products axis can aggravate infarct size and postinfarction remodeling.4 Considering the activation of receptor for advanced glycation end products contributing to the expression and release of S100A8 and S100A9, it could be worth identifying the initial upstream bioactive molecule of MI-induced positive feedback loop of granulopoiesis between cardiac neutrophils and granulocyte precursors in bone marrow or other S100 proteins, which might affect the dynamic changes of S100A8/A9 in the cardiac environment or circulation and synergistically contribute to the progression of cardiac remodeling, for broadening our understanding of a larger network of S100 proteins with cardiovascular effects in the setting of MI. Although disruption of S100A8/A9 signaling in a mouse model of permanent ligation of the left anterior descending artery could suppress MI-induced granulopoiesis and have favorable outcomes on the heart, as evidence supporting the short-term hypertrophic preconditioning by transverse aortic constriction in providing potent cardioprotection against subsequent hypertrophic stress through upregulation of S100A8/A9 protein expression becomes available,5 investigating whether the ability of S100A8/A9 targeting to modulate cardiovascular disease outcomes appears to be context specific, which is likely to be more effective in patient subpopulations with sustained and excessive cardiac injury and no history © 2020 American Heart Association, Inc. LETTER TO THE EDITOR