德国慕尼黑大学医学院Jovica Ninkovic研究小组在研究中取得进展。他们的研究发现TDP-43凝聚物和脂滴调节创伤性脑损伤后小胶质细胞的反应性和再生。这一研究成果于2022年11月24日发表在国际学术期刊《自然-神经科学》上。

研究人员在斑马鱼中使用刺伤损伤模型确定了损伤诱导小胶质细胞的状态，其特征是脂滴和43kDa 凝聚物TAR DNA结合蛋白（TDP-43）⁺的积累。颗粒介导的脂滴和TDP-43⁺缩合物的清除是必要的，其足以促进小胶质细胞恢复到基底状态并实现无疤痕再生。此外，在创伤性脑损伤患者的死亡后皮质脑组织中，小胶质细胞的活化程度与脂滴和TDP-43 ⁺凝聚物的积累相关。

总之，该研究结果揭示了损伤后小胶质细胞恢复到未激活状态所需的机制，这有可能在人类中产生新的治疗应用。

研究人员表示，减少病理性激活小胶质细胞的活化对于预防慢性炎症和组织瘢痕形成至关重要。

附：英文原文

Title: TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury

Author: Zambusi, Alessandro, Novoselc, Klara Tereza, Hutten, Saskia, Kalpazidou, Sofia, Koupourtidou, Christina, Schieweck, Rico, Aschenbroich, Sven, Silva, Lara, Yazgili, Ayse Seda, van Bebber, Frauke, Schmid, Bettina, Mller, Gabriel, Tritscher, Clara, Stigloher, Christian, Delbridge, Claire, Sirko, Swetlana, Gnes, Zeynep Irem, Liebscher, Sabine, Schlegel, Jrgen, Aliee, Hananeh, Theis, Fabian, Meiners, Silke, Kiebler, Michael, Dormann, Dorothee, Ninkovic, Jovica

Issue&Volume: 2022-11-24

Abstract: Decreasing the activation of pathology-activated microglia is crucial to prevent chronic inflammation and tissue scarring. In this study, we used a stab wound injury model in zebrafish and identified an injury-induced microglial state characterized by the accumulation of lipid droplets and TAR DNA-binding protein of 43kDa (TDP-43)+ condensates. Granulin-mediated clearance of both lipid droplets and TDP-43+ condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration. Moreover, in postmortem cortical brain tissues from patients with traumatic brain injury, the extent of microglial activation correlated with the accumulation of lipid droplets and TDP-43+ condensates. Together, our results reveal a mechanism required for restoring microglia to a nonactivated state after injury, which has potential for new therapeutic applications in humans.

DOI: 10.1038/s41593-022-01199-y

Source: https://www.nature.com/articles/s41593-022-01199-y