Department of Physiology and Biophysics, Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, AR 72202, United States.
Immunol Lett. 2011 Jun 30;137(1-2):15-27. doi: 10.1016/j.imlet.2011.01.015. Epub 2011 Jan 31.
OxLDL binding to CD36 is shown to result in macrophage activation and foam cell formation that have been implicated in atherosclerosis. However, CD36 has also been shown to induce inflammatory response to other ligands besides oxLDL. During the course of blocking CD36 oxLDL binding function using anti CD36 antibodies, we have identified a novel domain of CD36 that triggers inflammatory response-independent of oxLDL binding. OxLDL bound to the mouse reporter cell line RAW-Blue induced TNF-α and RANTES mRNA and protein expression. Pretreatment of RAW-Blue cells with an anti-mCD36 mAb, JC63.1, an activating mCD36 mAb, surprisingly did not inhibit oxLDL-induced response. Further, binding of this antibody to CD36 alone induced a pro-inflammatory cytokine response in RAW-Blue cells as well as primary mouse macrophages. The induction of cytokine response was specific only to this antibody and was CD36-dependent, since CD36(-/-) macrophages failed to induce a similar response. The interaction of the antibody to CD36 led to activation of NF-κB and MAP kinase. Notably, a CD36 peptide blocked oxLDL-induced foam cell formation and macrophage activation. However, the activating mCD36 mAb induced macrophage activation was not inhibited by CD36 peptide. Further, activating mCD36 mAb enhanced oxLDL- or TLR2- or TLR4-mediated inflammatory responses. Collectively, our data provide evidence that activating mCD36 mAb binds to a domain different from the oxLDL-binding domain on mouse CD36, and suggest that interaction at this domain may contribute to oxLDL-independent macrophage inflammatory responses that lead to chronic inflammatory diseases.
氧化低密度脂蛋白（OxLDL）与 CD36 的结合被证明会导致巨噬细胞的激活和泡沫细胞的形成，这与动脉粥样硬化有关。然而，CD36 也被证明会对除 OxLDL 以外的其他配体诱导炎症反应。在使用抗 CD36 抗体阻断 CD36 与 OxLDL 的结合功能的过程中，我们发现了 CD36 的一个新结构域，该结构域可以触发与 OxLDL 结合无关的炎症反应。OxLDL 与小鼠报告细胞系 RAW-Blue 结合，诱导 TNF-α 和 RANTES mRNA 和蛋白的表达。用抗 mCD36 mAb（JC63.1）预处理 RAW-Blue 细胞，该 mAb 是一种激活 mCD36 的 mAb，出人意料的是，它并没有抑制 OxLDL 诱导的反应。此外，该抗体与 CD36 的结合会在 RAW-Blue 细胞以及原代小鼠巨噬细胞中引起促炎细胞因子的反应。这种细胞因子反应的诱导仅对该抗体特异，并且依赖于 CD36，因为 CD36(-/-)巨噬细胞无法诱导类似的反应。抗体与 CD36 的相互作用导致 NF-κB 和 MAP 激酶的激活。值得注意的是，CD36 肽阻断了 OxLDL 诱导的泡沫细胞形成和巨噬细胞激活。然而，激活 mCD36 mAb 诱导的巨噬细胞激活不能被 CD36 肽抑制。此外，激活 mCD36 mAb 增强了 OxLDL 或 TLR2 或 TLR4 介导的炎症反应。总的来说，我们的数据提供了证据，表明激活 mCD36 mAb 结合到小鼠 CD36 上不同于 OxLDL 结合域的一个结构域，并且表明该结构域的相互作用可能导致与 OxLDL 无关的巨噬细胞炎症反应，从而导致慢性炎症性疾病。
