https://ror.org/04gyf1771 Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA.
Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA.
Life Sci Alliance. 2024 Sep 6;7(11). doi: 10.26508/lsa.202402788. Print 2024 Nov.
Sickle cell disease (SCD) is the most common inherited monogenetic disorder. Chronic and acute pain are hallmark features of SCD involving neural and vascular injury and inflammation. Mast cells reside in the vicinity of nerve fibers and vasculature, but how they influence these structures remains unknown. We therefore examined the mechanism of mast cell activation in a sickle microenvironment replete with cell-free heme and inflammation. Mast cells exposed to this environment showed an explosion of nuclear contents with the release of citrullinated histones, suggestive of mast cell extracellular trap (MCET) release. MCETs interacted directly with the vasculature and nerve fibers, a cause of vascular and neural injury in sickle cell mice. MCET formation was dependent upon peptidylarginine deiminase 4 (PAD4). Inhibition of PAD4 ameliorated vasoocclusion, chronic and acute hyperalgesia, and inflammation in sickle mice. PAD4 activation may also underlie neutrophil trap formation in SCD, thus providing a novel target to treat the sequelae of vascular and neural injury in SCD.
镰状细胞病（SCD）是最常见的遗传性单基因疾病。慢性和急性疼痛是 SCD 的标志性特征，涉及神经和血管损伤和炎症。肥大细胞存在于神经纤维和血管附近，但它们如何影响这些结构尚不清楚。因此，我们研究了富含游离血红素和炎症的镰状细胞微环境中肥大细胞激活的机制。暴露于这种环境中的肥大细胞显示出核内容物的爆炸，伴随着瓜氨酸化组蛋白的释放，提示肥大细胞细胞外陷阱（MCET）的释放。MCETs 与血管和神经纤维直接相互作用，这是导致镰状细胞小鼠血管和神经损伤的原因。MCET 的形成依赖于肽基精氨酸脱亚氨酶 4（PAD4）。PAD4 的抑制可改善镰状细胞小鼠的血管阻塞、慢性和急性痛觉过敏以及炎症。PAD4 的激活也可能是 SCD 中性粒细胞陷阱形成的基础，从而为治疗 SCD 中血管和神经损伤的后遗症提供了一个新的靶点。
