Chen Shaokui, Liao Ping, Xi Long, Yang Yang, Wu Wenzhong, Islam Md Sahidul, Lin Zibei, Zheng Ying, Chen Xin
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China.
Shenzhen Second People's Hospital, Shenzhen 518035, Guangdong Province, China.
Rheumatol Immunol Res. 2022 Dec 31;3(4):190-197. doi: 10.2478/rir-2022-0034. eCollection 2022 Dec.
Topical administration of Tacrolimus (TAC) is efective in the treatment of psoriasis in human patients and in mouse models. Previously, we showed that, though promoting the proliferative expansion of CD4Foxp3 regulatory T cells (Tregs), TNFR2 was protective in mouse psoriasis model. We thus examined the role of TNFR2 signal in the efect of TAC in the treatment of mouse psoriasis.
To this end, psoriasis was induced in WT, or TNFR1 KO, or TNFR2 KO mice, and the psoriatic mice were treated with or without IMQ.
The results showed that TAC treatment potently inhibited the development of psoriasis in WT and TNFR1 KO mice, but not in TNFR2 KO mice. However, the treatment of TAC failed to induce the expansion of Tregs in psoriatic mice. In addition to playing a decisive role in the activation of Tregs, TNFR2 stimulates the generation and activation of myeloid-derived suppressor cells (MDSCs). This led us to found that the topical treatment with TAC markedly increased the number of MDSCs in the spleen of WT and TNFR1 KO mice, but not in TNFR2 KO mice. Consequently, TAC potently decreased serum levels of IL-17A, INF-γ, and TNF and their mRNA levels in the inflamed skin lesion.
Therefore, our study for the first time found that the therapeutic efect of TAC in psoriasis is associated with the expansion of MDSCs in a TNFR2-dependent manner.
在人类患者和小鼠模型中，外用他克莫司（TAC）对银屑病的治疗有效。此前，我们发现，虽然肿瘤坏死因子受体2（TNFR2）可促进CD4Foxp3调节性T细胞（Tregs）的增殖性扩增，但在小鼠银屑病模型中具有保护作用。因此，我们研究了TNFR2信号在TAC治疗小鼠银屑病效果中的作用。
为此，在野生型（WT）、TNFR1基因敲除（KO）或TNFR2 KO小鼠中诱导银屑病，并对银屑病小鼠进行咪喹莫特（IMQ）处理或不处理。
结果显示，TAC治疗可有效抑制WT和TNFR1 KO小鼠银屑病的发展，但对TNFR2 KO小鼠无效。然而，TAC治疗未能诱导银屑病小鼠中Tregs的扩增。除了在Tregs的激活中起决定性作用外，TNFR2还刺激骨髓来源的抑制细胞（MDSCs）的产生和激活。这使我们发现，TAC局部治疗可显著增加WT和TNFR1 KO小鼠脾脏中MDSCs的数量，但对TNFR2 KO小鼠无效。因此，TAC可有效降低炎症性皮肤病变中白细胞介素-17A（IL-17A）、干扰素-γ（INF-γ）和肿瘤坏死因子（TNF）的血清水平及其mRNA水平。
因此，我们的研究首次发现，TAC治疗银屑病的效果与以TNFR2依赖的方式扩增MDSCs有关。
