【作者】 刘娟；

【导师】 陆前进；

【作者基本信息】 中南大学 ， 皮肤病与性病学， 2023， 硕士

【摘要】 背景:特应性皮炎(Atopic dermatitis,AD)是一种慢性复发性的炎症性皮肤病,其临床特征为慢性瘙痒、出现湿疹样皮疹。AD的临床表现复杂、病因尚不明确,容易反复的病程和长期的慢性瘙痒给个人和社会带来了极大的负担。传统的系统用药如免疫抑制剂和糖皮质激素,因其全身的不良反应,限制了其广泛应用。近年来,基于JAK-STAT信号通路对AD发病机制的重要性,越来越多的JAK抑制剂被研究用于治疗AD。基于作用靶点的不同,靶向JAK1受体可以阻断IL-4,IL-13和干扰素信号通路,是治疗AD的主要靶点。靶向JAK2受体会抑制血细胞生成,主要用于血液系统肿瘤的治疗。靶向JAK3受体可能降低对感染和肿瘤的防御作用。靶向TYK2受体,可抑制Th17或Th22型免疫反应,可能影响固有免疫和适应性免疫细胞的成熟。单靶点的选择性JAK1抑制剂对以Th17或Th22型免疫反应为主的AD患者疗效欠佳。靶向TYK2和JAK1受体抑制剂的组合具有抑制IL-12和IL-23通路的潜力,且副作用小,这可能为AD的治疗提供了新的靶点。目的:探究新型双靶点Tyk2/Jak1抑制剂TLL041对MC903诱导的AD样小鼠模型的治疗作用及其潜在的机制。方法:(1)观察口服灌胃Tyk2/Jak1抑制剂TLL041对MC903诱导的小鼠AD样皮损形成的影响:①将8周龄的雌性Balb/c小鼠随机分为四组,包括对照组(Control,Ctrl)、10 mg/kg TLL041 组(L-TLL041)、20 mg/kg TLL041 组(H-TLL041)和地塞米松组(Dexamethasone,Dex)。所有组别的小鼠双耳涂抹等量的MC903。在造模过程中,L-TLL041组和H-TLL041组小鼠分别一天两次灌胃10 mg/kg或20 mg/kg的TLL041,Dex组小鼠一天一次灌胃2 mg/kg的地塞米松,Ctrl组一天两次灌胃等量的0.5%羟丙基甲基纤维素;②拍照记录不同处理组小鼠皮损表现情况,造模13天后处死小鼠,收集造模部位皮损组织;③对皮损组织进行HE染色,观察其组织病理改变;④利用免疫荧光染色技术检测皮损组织中CD3、CD11b、Ly6G和Filaggrin染色情况;⑤将小鼠皮损组织制备为单细胞悬液,流式细胞术检测不同处理组小鼠皮损部位Th1、Th2、Th17、CD11b+、F4/80+、Gr-1+、Sigliec-F+等细胞的频率和数量变化。(2)明确口服灌胃Tyk2/Jak1抑制剂TLL041对MC903诱导的AD样小鼠的颈部引流淋巴结和脾脏的影响:①通过流式细胞术检测小鼠淋巴结和脾脏中Th1/Th2/Th17的细胞频率和数量的变化;②通过流式细胞术检测小鼠淋巴结和脾脏中B细胞亚群的细胞频率和数量的变化。(3)探究各组小鼠皮损相关基因转录组水平间的差异:①对各组小鼠的皮损组织提取总RNA后,运用RT-qPCR(Reverse transcription-quantitative PCR)检测AD相关的细胞因子(IL-4、IL-13、IL-5、IL-17)以及相对应的转录因子(Gata3、Rorα、T-bet、Rorγt)的mRNA表达水平;②运用RT-qPCR技术检测JAK-STAT通路相关的受体及转录因子(Jak1、Tyk2、Stat1、Stat2、Stat3、Stat6)的mRNA表达水平;③运用RT-qPCR技术检测AD瘙痒相关的基因Mrgpra2b和皮肤屏障相关基因Filaggrin的mRNA表达水平;④选取Ctrl组和H-TLL041组的总RNA进行转录组测序,筛选差异表达基因,并对差异表达基因进行通路富集分析。结果:(1)口 服灌胃 10 mg/kg或20 mg/kg的Tyk2/Jak1抑制剂TLL041 能显著抑制AD小鼠皮损形成:①自造模Day8起,相比于Ctrl组,L-TLL041组皮损严重程度评分显著降低(P<0.05),在H-TLL041组及Dex组显著降低(P<0.001);②HE染色结果表明,相比于Ctrl组,L-TLL041组和H-TLL041组小鼠皮损组织表皮厚度显著下降(P<0.05);③皮损多重免疫荧光染色结果表明:相对于Ctrl组,L-TLL041组和H-TLL041组小鼠皮损中的CD3+ T细胞、CD11b+及CD1 1b+Ly6G+炎症细胞浸润数量显著减少(P<0.05);④皮肤组织流式细胞术结果显示:相比于Ctrl组,在H-TLL041组小鼠皮损中CD3+T和CD11b+Gr-1+占淋巴细胞的频率显著降低(P<0.05),在L-TLL041 和Dex组内无统计学差异(P>0.05);L-TLL041和H-TLL041组小鼠皮损中CD11b+F4/80+占淋巴细胞的频率显著降低(P<0.05),在Dex组无统计学差异(P>0.05);L-TLL041 和H-TLL041组小鼠皮损中CD11b+Siglec-F+占淋巴细胞的频率显著降低(P<0.01),在Dex组无统计学差异(P>0.05);相比于Ctrl组,在L-TLL041和H-TLL041 组中CD3+T、CD11b+F4/80+和CD11b+Gr-1+细胞的数量显著降低(P<0.05),在Dex组无统计学差异(P>0.05);CD11b+Siglec-F+细胞的数量在L-TLL041组中显著降低(P<0.05),在H-TLL041显著降低(P<0.01),在Dex组无统计学差异(P>0.05);⑤皮肤组织流式细胞术结果表明:相比于Ctrl组,在L-TLL041组和H-TLL041组小鼠皮损中CD3+CD4+T细胞占淋巴细胞的频率无显著变化(P>0.05),在Dex组显著降低(P<0.05);所有治疗组皮损中Th1/Th2/Th17细胞占CD3+CD4+T细胞的频率无统计学差异(P>0.05);相比于Ctrl组,在L-TLL041组和H-TLL041组小鼠皮损中CD3+CD4+T细胞数量显著减少(P<0.01),在Dex组显著减少(P<0.05);在所有治疗组皮损中Th1细胞数量无统计学差异(P>0.05);在L-TLL041组和H-TLL041组小鼠皮损中Th2细胞数量显著减少(P<0.01),在Dex组显著减少(P<0.05);在H-TLL041和Dex组小鼠皮损中Th17细胞数量显著减少(P<0.05),在L-TLL041组减少,但是无统计学意义(P>0.05)。(2)口服灌胃 10 mg/kg或20 mg/kg的Tyk2/Jak1抑制剂TLL041 均能显著降低AD小鼠引流淋巴结中Th细胞亚群及B细胞的数量,对脾脏无明显影响:①相比于Ctrl组,所有治疗组的引流淋巴结和脾脏中Th1/Th2/Th17细胞占CD3+CD4+T细胞的频率无统计学差异(P>0.05);在H-TLL041和Dex组小鼠引流淋巴结中Th1细胞数量显著减少(P<0.01),在L-TLL041组数量显著减少(P<0.05);在H-TLL041和Dex组小鼠淋巴结中Th2细胞数量显著减少(P<0.05),在L-TLL041组无明显差异(P>0.05);在H-TLL041组小鼠淋巴结中Th17细胞数量显著减少(P<0.05),在Dex组显著减少(P<0.001);在H-TLL041组小鼠淋巴结中CD3-IL-4+数量显著减少(P<0.01),在Dex组显著减少(P<0.05),在L-TLL041组无明显差异(P>0.05);相比于Ctrl组,治疗组的脾脏中Th1/Th2/Th17细胞的数量无统计学差异(P>0.05);②相比于Ctrl组,在所有治疗组小鼠引流淋巴结和脾脏中,Naive B、Memory B、GCB和Active B细胞频率无明显差异(P>0.05);在L-TLL041的小鼠脾脏和淋巴结中PC细胞频率均显著降低(P<0.05),在H-TLL041组小鼠淋巴结中显著降低(P<0.05),在Dex组的小鼠脾脏和淋巴结中无明显差异(P>0.05);在L-TLL041组小鼠脾脏中Plasmablast细胞频率显著降低(P<0.05),在H-TLL041组和Dex组无明显差异(P>0.05);相比于Ctrl组,在所有治疗组小鼠淋巴结中Plasmablast细胞数量无明显差异(P>0.05);在L-TLL041组小鼠淋巴结中Na(?)ve B、Active B及PC细胞数量显著减少(P<0.05),Memory B和GC B数量显著减少(P<0.01);在H-TLL041组小鼠淋巴结中Naive B、Memory B、Active B、GCB及PC细胞数量显著减少(P<0.05);Dex组小鼠淋巴结中Naive B、Memory B及GCB细胞数量显著减少(P<0.01),Active B细胞数量显著减少(P<0.001),PC细胞数量无明显差异(P>0.05);相对于Ctrl组,所有治疗组小鼠脾脏中Active B细胞数量无明显差异(P>0.05);在Dex组脾脏中Naive B、Memory B及GCB细胞数量显著减少(P<0.05),而在L-TLL041和H-TLL041组中无明显差异(P>0.05);在L-TLL041和H-TLL041组脾脏中Plasmablast细胞数量显著减少(P<0.01),在Dex组中显著减少(P<0.05);在L-TLL041和Dex组脾脏中PC细胞数量显著减少(P<0.05),而在L-TLL041组无明显差异(P>0.05);(3)口服灌胃Tyk2/Jak1抑制剂TLL041下调AD小鼠皮损中细胞因子及其受体信号通路,上调皮肤屏障相关基因的转录组水平。①RT-qPCR结果显示:相对于Ctrl组,在L-TLL041和H-TLL041组皮损中Il4 mRNA表达水平显著下降(P<0.001),在Dex组显著降低(P<0.01);在所有治疗组皮损中Il13 mRNA表达水平显著下降(P<0.01);在H-TLL041和Dex组皮损中Il17a mRNA表达水平显著下降(P<0.001),在L-TLL041组无明显变化(P>0.05);在所有治疗组皮损中Il5 mRNA表达水平无显著差异(P>0.05);②检测JAK-STAT通路中相关的受体和转录因子mRNA表达水平,QPCR结果显示:相对于Ctrl组,所有治疗组小鼠皮损处Jakl、Tyk2、Stat1、Stat6表达水平无统计学差异(P>0.05);在H-TLL041组小鼠皮损处Stat2表达水平显著降低(P<0.05),在L-TLL041组和Dex组无明显差异(P>0.05);在Dex组小鼠皮损处Stat3表达水平显著降低(P<0.05),在L-TLL041组和H-TLL041组无统计学差异(P>0.05);③检测调控Th亚群分化的转录因子mRNA表达水平,qPCR结果表明:相对于Ctrl组,所有治疗组皮损处Gata3表达水平无统计学差异(P>0.05);在H-TLL041组皮损处Rorα表达水平显著降低(P<0.01),在Dex组显著降低(P<0.001),在L-TLL041组无统计学差异(P>0.05);在H-TLL041组皮损处T-bet表达水平显著降低(P<0.05),在Dex组显著降低(P<0.01),在L-TLL041组无统计学差异(P>0.05);在H-TLL041组皮损处Rorγt表达水平显著降低(P<0.05),在L-TLL041组和Dex组无统计学差异(P>0.05);④RT-qpcr结果显示:与Ctrl组相比,皮肤屏障相关的Filaggrin表达水平在H-TLL041和Dex组显著升高(P>0.05);与瘙痒相关的Mrgpra2b表达水平在Dex组显著降低(P<0.05),在H-TLL041组降低,但是无统计学意义(P>0.05);⑤转录组测序结果显示:相对于Ctrl组,与表皮屏障相关(Loricrin、Flg2、Cldn23)的基因转录组表达水平在H-TLL041组均明显上调。GO分析表明,H-TLL041组下调的差异基因主要富集于细胞因子及其受体信号通路、STAT磷酸化信号通路等。结论:靶向Tyk2/Jak1受体的新型小分子抑制剂TLL041,通过减少Th细胞和B细胞亚群数量从而改善MC903诱导的AD样模型小鼠的皮损,是治疗AD的潜在小分子抑制剂。图36幅,表26个,参考文献51篇更多还原

【Abstract】 Background:Atopic dermatitis(AD)is a chronic relapsing inflammatory skin disease characterized by chronic itching and the appearance of eczematous lesions.The clinical manifestations of AD are complex,and the etiology remains unclear.The recurrent course and longterm chronic itching of AD impose a significant burden on individuals and society.Traditional systemic medications,such as immunosuppressants and glucocorticoids,have limited widespread use due to their systemic adverse effects.In recent years,the importance of the JAK-STAT signaling pathway in the pathogenesis of AD has led to increasing research on JAK inhibitors for the treatment of AD.Depending on the specific target,targeting the JAK1 receptor can block the IL-4,IL-13,and interferon signaling pathways,making it a key target for AD treatment.Targeting JAK2 inhibits blood cell production and is mainly used in the treatment of hematologic malignancies.Targeting JAK3 may reduce defense against infections and tumors.Targeting TYK2 can inhibit Th17 or Th22 immune responses,which may affect the maturation of innate and adaptive immune cells.Selective JAK1 inhibitors alone have shown limited efficacy in AD patients with predominant Th17 or Th22 immune responses.Combination therapy with TYK2 and JAK1 inhibitors has the potential to inhibit the IL12 and IL-23 pathways with minimal side effects,providing new targets for the treatment of AD.Objective:This study aims to investigate the therapeutic effects and mechanisms of a novel dual-target Tyk2/Jak1 inhibitor TLL041 on the mouse model of AD induced by MC903.Methods:(1)Observation of the effects of oral gavage of Tyk2/Jak1 inhibitor TLL041 on the formation of AD-like skin lesions induced by MC903 in mice.①Eight-week-old female Balb/c mice were divided into four groups:control group(Ctrl),10 mg/kg TLL041 group(L-TLL041),20 mg/kg TLL041 group(H-TLL041),and dexamethasone group(Dex).All groups of mice were topically treated with equal amounts of MC903.During the modeling process,mice in the L-TLL041 group and H-TLL041 group were orally gavaged with 10 mg/kg or 20 mg/kg of TLL041 twice a day,respectively,and mice in the Dex group were orally gavaged with 2 mg/kg of dexamethasone once a day.②Photographs were taken to record the skin lesions of mice in different treatment groups,and after the modeling was completed,the mice were euthanized,and the skin lesion tissues were collected.③HE staining was performed on the skin lesion tissues to observe the histopathological changes.④Immunofluorescence staining of CD3,CD11b,Ly6G,and Filaggrin in skin lesion tissues was used to observe lymphocyte infiltration and skin barrier improvement at the lesion site.⑤The skin lesion tissues of the mice were prepared into single-cell suspensions,and flow cytometry was used to detect the frequency and quantity changes of Th1,Th2,Th17,CD11b+,F4/80+,Gr-1+,Siglec-F+cells in different treatment groups.(2)Clarify the effects of oral gavage Tyk2/Jak1 inhibitor TLL041 on draining lymph nodes and spleen in MC903-induced AD-like mice.①Detect changes in the frequencies and numbers of Th1/Th2/Th17 cells in mouse lymph nodes and spleen by flow cytometry.②Detect changes in the frequencies and numbers of B cell subsets in mouse lymph nodes and spleen by flow cytometry.(3)Observe the differences in transcriptome levels of skin lesionrelated genes among different groups of mice.①Extract total RNA from the skin lesion tissue of each group of mice and use RT-qPCR(Reverse transcription-quantitative PCR)to detect the mRNA expression levels of AD-related cytokines(Il4,Il13,Il5,Il17a)and their corresponding transcription factors(Gata3,Rorα,T-bet,Roryt).②Use RT-qPCR to detect the mRNA expression levels of JAK-STAT pathway-related receptors and transcription factors(Jak1,Tyk2,Stat1,Stat2,Stat3,Stat6).③Use RTqPCR to detect the mRNA expression levels of AD-related itch gene Mrgpra2b and skin barrier-related gene Filaggrin.④Select total RNA from Ctrl group and H-TLL041 group for transcriptome sequencing,screen for differentially expressed genes,and perform pathway enrichment analysis on differentially expressed genes.Results:(1)Oral gavage of Tyk2/Jak1 inhibitor TLL041 at doses of 10 mg/kg or 20 mg/kg significantly inhibited AD skin lesion formation in mice.①Treatment with the Tyk2/Jak1 inhibitor TLL041 at doses of 10 mg/kg or 20 mg/kg significantly reduced the clinical symptoms and severity scores of skin lesions in AD mice.②HE staining results showed that systemic administration of 10 mg/kg or 20 mg/kg TLL041 significantly improved epidermal thickening(P<0.05).③Multiple immunofluorescence staining of skin lesions showed that compared to the Ctrl group,the number of CD3+T cells,CD11b+ cells,and CD11b+Ly6G+inflammatory cells in the skin lesions of the L-TLL041 and H-TLL041 groups was significantly reduced(P<0.05).④Compared to the Ctrl group,the proportion of CD3+ T cells and CD11b+Gr-1+cells in mouse skin significantly decreased in the H-TLL041 group(P<0.05);The proportion of CD11b+F4/80+cells in lymphocytes significantly decreased in the L-TLL041 and H-TLL041 groups(P<0.05).The proportion of CD11b+Siglec-F+cells in lymphocytes significantly decreased in the L-TLL041 and H-TLL041 groups(P<0.01),with no significant differences in the Dex group(P>0.05).Compared to the Ctrl group,the numbers of CD3+T cells,CD11b+F4/80+cells,and CD11b+Gr-1+ cells significantly decreased in the L-TLL041 and HTLL041 groups(P<0.05),with no significant differences in the Dex group(P>0.05).The number of CD11b+Siglec-F+cells significantly decreased in the L-TLL041 group(P<0.05)and the H-TLL041 group(P<0.01),with no significant differences in the Dex group(P>0.05).⑤Compared with the Ctrl group,there was no significant change in the frequency of CD3+CD4+T cells among lymphocytes in skin lesions of mice in the L-TLL041 and H-TLL041 groups(P>0.05),while a significant decrease was observed in the Dex group(P<0.05).There was no statistical difference in the frequency of Th1/Th2/Th17 cells among CD3+CD4+T cells in skin lesions of all treatment groups(P>0.05).Compared with the Ctrl group,the number of CD3+CD4+T cells in skin lesions significantly decreased in the L-TLL041 and H-TLL041 groups(P<0.01)and in the Dex group(P<0.05).There was no statistical difference in the number of Th1 cells in skin lesions of all treatment groups(P>0.05).The number of Th2 cells in skin lesions significantly decreased in the LTLL041 and H-TLL041 groups(P<0.01)and in the Dex group(P<0.05).The number of Th17 cells significantly decreased in the H-TLL041 and Dex groups(P<0.05)and in the L-TLL041 group but without statistical significance(P>0.05).(2)The Tyk2/Jak1 inhibitor TLL041 administered orally at doses of 10 mg/kg or 20 mg/kg significantly reduced the number of Th subsets and B cells in the draining lymph nodes(dLNs)of AD mice,with no significant effect on the spleen.①Compared with the Ctrl group,there was no statistical difference in the frequency of Th1/Th2/Th17 cells among CD3+CD4+T cells in dLNs and spleens of mice in all treatment groups(P>0.05).The number of Thl cells significantly decreased in dLNs of mice in the H-TLL041 and Dex groups(P<0.01)and in the L-TLL041 group(P<0.05).The number of Th2 cells significantly decreased in dLNs of mice in the H-TLL041 and Dex groups(P<0.05)and showed no significant difference in the LTLL041 group(P>0.05).The number of Th17 cells significantly decreased in dLNs of mice in the H-TLL041 group(P<0.05)and in the Dex group(P<0.001).The number of CD3-IL-4+ cells significantly decreased in the dLNs of mice in the H-TLL041(P<0.01)and Dex groups(P<0.05)and showed no significant difference in the L-TLL041 group(P>0.05).Compared with the Ctrl group,there was no statistical difference in the number of Th1/Th2/Th17 cells in the spleens of all treatment groups(P>0.05).②Compared with the Ctrl group,there were no significant differences in the frequencies of Naive B,Memory B,GCB,and Active B cells in the dLNs and spleen of all treatment groups in mice(P>0.05).The frequency of PC cells was significantly decreased in the spleen and dLNs of mice treated with L-TLL041(P<0.05),and in the dLNs of mice treated with HTLL041(P<0.05),but not in the spleen and dLNs of mice treated with Dex(P>0.05).The frequency of Plasmablast cells was significantly decreased in the spleen of mice treated with L-TLL041(P<0.05),but not in mice treated with H-TLL041 and Dex(P>0.05).There were no significant differences in the number of Plasmablast cells in the dLNs of all treatment groups compared with the Ctrl group(P>0.05).In the spleen of mice treated with L-TLL041,the number of Naive B,Active B,and PC cells was significantly decreased(P<0.05),and the number of Memory B and GC B cells was significantly decreased(P<0.01).In the dLNs of mice treated with H-TLL041,the number of Naive B,Memory B,Active B,GC B,and PC cells was significantly decreased(P<0.05).In the dLNs of mice treated with Dex,the number of Naive B,Memory B,and GC B cells was significantly decreased(P<0.01),the number of Active B cells was significantly decreased(P<0.001),and the number of PC cells was not significantly different(P>0.05).③Compared with the Ctrl group,there were no significant differences in the number of Active B cells in the spleen of all treatment groups(P>0.05).In the spleen of mice treated with Dex,the number of Naive B,Memory B,and GC B cells was significantly decreased(P<0.05),but not in the spleen of mice treated with L-TLL041 and H-TLL041(P>0.05).The number of PC cells was significantly decreased in the spleen of mice treated with L-TLL041 and Dex(P<0.05),but not in the spleen of mice treated with L-TLL041(P>0.05).(3)The Tyk2/Jak1 inhibitor TLL041 administered orally at a dose of 20 mg/kg downregulates cytokine and receptor signaling pathways in the skin lesions of AD mice,while upregulating the transcriptional levels of genes related to the skin barrier.①Compared with the Ctrl group,the mRNA expression levels of Il4 in skin lesions were significantly decreased in the L-TLL041 and HTLL041 groups(P<0.001),and in the Dex group(P<0.01);the mRNA expression levels of Il13 in skin lesions of all treatment groups were significantly decreased(P<0.01);the mRNA expression levels of Il17a in skin lesions were significantly decreased in the H-TLL041 and Dex groups(P<0.001),while no significant change was observed in the L-TLL041 group(P>0.05);the mRNA expression levels of Il5 in skin lesions of all treatment groups showed no significant difference(P>0.05).②The mRNA expression levels of JAK-STAT pathway-related receptors and transcription factors showed that compared with the Ctrl group,there were no statistical differences in the expression levels of Jak1,Tyk2,Stat1,and Stat6 in skin lesions of all treatment groups(P>0.05).The expression level of Stat2 in skin lesions of the H-TLL041 group was significantly decreased(P<0.05),while there was no significant difference in the L-TLL041 and Dex groups(P>0.05).The expression level of Stat3 in skin lesions of the Dex group was significantly decreased(P<0.05),while there was no statistical difference in the L-TLL041 and H-TLL041 groups(P>0.05).③The mRNA expression levels of transcription factors that regulate Th subset differentiation showed that compared with the Ctrl group,there were no statistical differences in the expression levels of Gata3 in skin lesions of all treatment groups(P>0.05).The expression level of Rorα in skin lesions was significantly decreased in the H-TLL041(P<0.01),and Dex group(P<0.001),and no statistical difference in the L-TLL041 group(P>0.05).The expression level of T-bet in skin lesions was significantly decreased in the H-TLL041(P<0.05),and Dex group(P<0.01),and no statistical difference in the L-TLL041 group(P>0.05).The expression level of Rorγt in skin lesions of the H-TLL041 group was significantly decreased(P<0.05),while there was no statistical difference in the LTLL041 and Dex groups(P>0.05).④Compared with the Ctrl group,the expression levels of Filaggrin related to skin barrier were significantly increased in the H-TLL041 and Dex groups(P<0.05);the expression level of Mrgpra2b related to itch was significantly decreased in the Dex group(P<0.05),while it was decreased in the H-TLL041 group,but without statistical significance(P>0.05).⑤Transcriptome sequencing results showed that compared to the Ctrl group,the transcriptome expression levels of genes related to the epidermal barrier(Loricrin,Flg2,Cldn23)were significantly upregulated in the HTLL041 group.GO analysis showed that the differentially downregulated genes in the H-TLL041 group were mainly enriched in cytokine and its receptor signaling pathways,STAT phosphorylation signaling pathways,etc.Conclusion:The JAK-STAT signaling pathway plays an important biological role in the pathogenesis of AD.A novel small molecule inhibitor TLL041 targeting Tyk2/Jak1 receptors improves skin lesions in a MC903induced AD-like mouse model by reducing the number of Th subpopulations and secretion of inflammatory cytokines.TLL041 may represent a potential small molecule therapy for treating AD.This thesis contains 36 graphs,27tables and 51references.更多还原