Department of Pathology, Diabetes and Obesity Center of Excellence, 815 Mercer St, University of Washington, Seattle, WA 98109-8055, USA.
Circulation. 2011 Mar 22;123(11):1216-26. doi: 10.1161/CIRCULATIONAHA.110.985523. Epub 2011 Mar 7.
S100A9 is constitutively expressed in neutrophils, dendritic cells, and monocytes; is associated with acute and chronic inflammatory conditions; and is implicated in obesity and cardiovascular disease in humans. Most of the constitutively secreted S100A9 is derived from myeloid cells. A recent report demonstrated that mice deficient in S100A9 exhibit reduced atherosclerosis compared with controls and suggested that this effect was due in large part to loss of S100A9 in bone marrow-derived cells.
To directly investigate the role of bone marrow-derived S100A9 in atherosclerosis and insulin resistance in mice, low-density lipoprotein receptor-deficient, S100A9-deficient bone marrow chimeras were generated. Neither atherosclerosis nor insulin resistance was reduced in S100A9-deficient chimeras fed a diet rich in fat and carbohydrates. To investigate the reason for this lack of effect, myeloid cells were isolated from the peritoneal cavity or bone marrow. S100A9-deficient neutrophils exhibited a reduced secretion of cytokines in response to toll-like receptor-4 stimulation. In striking contrast, S100A9-deficient dendritic cells showed an exacerbated release of cytokines after toll-like receptor stimulation. Macrophages rapidly lost S100A9 expression during maturation; hence, S100A9 deficiency did not affect the inflammatory status of macrophages.
S100A9 differentially modifies phenotypic states of neutrophils, macrophages, and dendritic cells. The effect of S100A9 deficiency on atherosclerosis and other inflammatory diseases is therefore predicted to depend on the relative contribution of these cell types at different stages of disease progression. Furthermore, S100A9 expression in nonmyeloid cells is likely to contribute to atherosclerosis.
S100A9 在中性粒细胞、树突状细胞和单核细胞中持续表达；与急性和慢性炎症状态相关；并与人类肥胖和心血管疾病有关。大多数持续分泌的 S100A9 来自于髓样细胞。最近的一份报告表明，与对照组相比，缺乏 S100A9 的小鼠表现出动脉粥样硬化程度降低，并表明这种效应在很大程度上归因于骨髓来源细胞中 S100A9 的缺失。
为了直接研究骨髓来源的 S100A9 在小鼠动脉粥样硬化和胰岛素抵抗中的作用，生成了低密度脂蛋白受体缺陷、S100A9 缺陷的骨髓嵌合体小鼠。在富含脂肪和碳水化合物的饮食喂养下，S100A9 缺陷嵌合体小鼠的动脉粥样硬化或胰岛素抵抗均未减少。为了研究这种缺乏效应的原因，从腹腔或骨髓中分离髓样细胞。S100A9 缺陷的中性粒细胞对 Toll 样受体-4 刺激的细胞因子分泌减少。相比之下，S100A9 缺陷的树突状细胞在 Toll 样受体刺激后表现出细胞因子的过度释放。巨噬细胞在成熟过程中迅速失去 S100A9 的表达；因此，S100A9 的缺乏并不影响巨噬细胞的炎症状态。
S100A9 差异调节中性粒细胞、巨噬细胞和树突状细胞的表型状态。因此，S100A9 缺乏对动脉粥样硬化和其他炎症性疾病的影响预计取决于这些细胞类型在疾病进展的不同阶段的相对贡献。此外，非髓样细胞中的 S100A9 表达可能有助于动脉粥样硬化的发生。
