From the Burke Neurological Institute, White Plains, NY (J.Y., E.K., C.B., S.C.).
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY (S.C.).
Stroke. 2019 Sep;50(9):2539-2546. doi: 10.1161/STROKEAHA.119.026053. Epub 2019 Jul 26.
Background and Purpose- Stroke-induced acute severe body weight (BW) loss is associated with a high rate of mortality during a critical poststroke period. Several interventions to reduce weight loss, however, have not been successful. Currently, the biological significance of this extraordinary catabolic process is not well understood. Spleen-derived monocytes/macrophages (MMs) are the major immune cells recruited to the injured brain. The trafficking of MMs has been shown to be important for tissue repair and recovery. The purpose of the study is to investigate whether the BW reduction is essential for MM-mediated immune response for mice to survive and whether a corticosterone-mediated catabolic event underlies the processes. Methods- C57BL/6 male mice (12-week-old) were subjected to transient middle cerebral artery occlusion. BW, total MMs, and their Ly-6C and Ly-6C subsets were determined in the spleen, blood, and the brain in poststroke mice. Poststroke survival rate and MM subsets were determined in mice with adrenalectomy, sham-adrenalectomy, and adrenalectomy mice supplemented with corticosterone. Results- Stroke reduced BW with a maximum reduction at day 3 poststroke (17.2±5.2%). The reduction at day 3 was positively linked to injury severity and selective depletion of MMs, but no other types of immune cells, in the spleen. Notably, the splenic MM depletion was significantly greater in mice with severe BW reduction (≥18% at day 3). In the blood, stroke depleted circulating MMs to a similar degree in animals with moderate and severe BW loss. Ly-6C+ monocyte infiltration in the poststroke brain was greater in mice with severe BW loss. Blocking the catabolic process by adrenalectomy significantly increased poststroke mortality, but the mortality was partially rescued by corticosterone supplement in adrenalectomy mice. Conclusions- Stroke-induced BW loss facilitates MM-mediated immune response, and the adrenal corticosterone-mediated catabolic process is necessary for poststroke survival. Visual Overview- An online visual overview is available for this article.
背景与目的- 卒中后急性严重体重（BW）下降与关键卒中后时期的高死亡率相关。然而，一些旨在减少体重下降的干预措施并未成功。目前，这种特殊的分解代谢过程的生物学意义尚不清楚。脾源性单核细胞/巨噬细胞（MMs）是募集到受损大脑的主要免疫细胞。已经表明 MMs 的迁移对于组织修复和恢复很重要。本研究的目的是研究 BW 减少是否对 MM 介导的免疫反应至关重要，以便使小鼠存活，以及皮质酮介导的分解代谢事件是否是该过程的基础。方法- 将 12 周龄的 C57BL/6 雄性小鼠进行短暂性大脑中动脉闭塞。在卒中后小鼠中测定 BW、总 MMs 及其 Ly-6C 和 Ly-6C 亚群在脾、血和脑中的含量。在肾上腺切除术、假手术和肾上腺切除术小鼠中补充皮质酮的情况下，测定卒中后生存率和 MM 亚群。结果- 卒中使 BW 下降，最大降幅出现在卒中后第 3 天（17.2±5.2%）。第 3 天的下降与损伤严重程度以及脾中 MMs 的选择性耗竭呈正相关，但脾中其他类型的免疫细胞无耗竭。值得注意的是，在 BW 严重下降（第 3 天≥18%）的小鼠中，脾 MM 耗竭更为明显。在血液中，在中度和重度 BW 损失的动物中，卒中使循环 MMs 耗竭到相似程度。在 BW 严重下降的小鼠中，卒中后大脑中的 Ly-6C+单核细胞浸润更为明显。通过肾上腺切除术阻断分解代谢过程会显著增加卒中后的死亡率，但在肾上腺切除术小鼠中补充皮质酮可部分挽救死亡率。结论- 卒中引起的 BW 下降促进了 MM 介导的免疫反应，而肾上腺皮质酮介导的分解代谢过程对于卒中后生存是必要的。
