Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
Department of Morphology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
Neurochem Int. 2021 Sep;148:105107. doi: 10.1016/j.neuint.2021.105107. Epub 2021 Jun 23.
Chemokines regulate infiltration of immune cells to brain in inflammation. Cathepsin C (CatC), a lysosomal protease, has been found to participate in neuroinflammation. However, how CatC affects chemokines expression in neuroinflammation triggered by traumatic brain injury (TBI) remains unclear. Here, we investigated the effects of CatC on chemokines and neuroinflammation in TBI.
The present study used CatC knockdown (KD) and overexpression (OE) mice to generate cryogenic brain lesion model and determined effects of CatC on expression of chemokines CCL2, CCL5 and CXCL2 and infiltration of immune cells in acute and chronic phases of the lesion. Further, cellular sources of various chemokines were demonstrated in vitro. Values were compared with wild type (WT) mice.
The results found that 6 h after lesion, CatC expression,IL-1β and TNF-α mRNA and protein expression were strongly induced in the lesions; CCL2 and CXCL2 mRNA and protein expression were increased in CatC OE mice, while decreased in CatC KD mice. On the 3rd day after lesion, macrophages and neutrophils were mainly infiltrated to the lesions. Simultaneously, Iba-1+ cells in CatC OE mice were increased, while MPO + cells in CatC KD mice were decreased. In contrast, on the 28th day after lesion, a few lymphocytes were infiltrated surrounding new blood vessels. CatC OE mice showed larger volumes of scar areas, higher expression of CCL2,CXCL2,IL-1β,TNF-α,IL-6 and iNOS, as well as stronger GFAP+ and Iba-1+ signals, while CatC KD mice had reversed effects. No significant differences of CCL5 expression were found in various genotype mice. Further, in vitro study demonstrated CatC-induced expression of CCL2 were mainly derived from microglia and neurons, while CXCL2 derived from microglia and astrocytes.
Our data indicate that CatC aggravates neuroinflammation via promoting production of CCL2 and CXCL2 in glial cells and neurons in a cryogenic brain lesion, providing potential cellular and molecular targets for future intervention of TBI and other neuroinflammatory diseases.
趋化因子调节炎症时免疫细胞向脑内浸润。组织蛋白酶 C（CatC），一种溶酶体蛋白酶，已被发现参与神经炎症。然而，CatC 如何影响创伤性脑损伤（TBI）引发的神经炎症中的趋化因子表达尚不清楚。在这里，我们研究了 CatC 对 TBI 中趋化因子和神经炎症的影响。
本研究使用 CatC 敲低（KD）和过表达（OE）小鼠生成冷冻脑损伤模型，并确定 CatC 对损伤急性期和慢性期各种趋化因子的表达和免疫细胞浸润的影响。此外，还在体外证明了各种趋化因子的细胞来源。将这些值与野生型（WT）小鼠进行比较。
结果发现，损伤后 6 小时，损伤部位的 CatC 表达、IL-1β 和 TNF-αmRNA 和蛋白表达强烈诱导；CatC OE 小鼠的 CCL2 和 CXCL2mRNA 和蛋白表达增加，而 CatC KD 小鼠的表达减少。损伤后第 3 天，巨噬细胞和中性粒细胞主要浸润到损伤部位。同时，CatC OE 小鼠中的 Iba-1+细胞增加，而 CatC KD 小鼠中的 MPO+细胞减少。相比之下，损伤后第 28 天，少量淋巴细胞浸润到新血管周围。CatC OE 小鼠表现出更大的疤痕区域体积、更高的 CCL2、CXCL2、IL-1β、TNF-α、IL-6 和 iNOS 表达以及更强的 GFAP+和 Iba-1+信号，而 CatC KD 小鼠则出现相反的效果。各种基因型小鼠的 CCL5 表达无明显差异。此外，体外研究表明，CatC 诱导的 CCL2 表达主要来自小胶质细胞和神经元，而 CXCL2 则来自小胶质细胞和星形胶质细胞。
我们的数据表明，CatC 通过促进冷冻脑损伤中小胶质细胞和神经元中 CCL2 和 CXCL2 的产生，加剧神经炎症，为未来干预 TBI 和其他神经炎症性疾病提供了潜在的细胞和分子靶点。
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