巨噬細胞參與癌症相關的發炎與牛皮癬發炎的分子 機制

以作者查詢圖書館館藏

、以作者查詢臺灣博碩士

、以作者查詢全國書目

、勘誤回報

、線上人數：137

、訪客IP：3.128.30.46

姓名

呂志豪(Chih-Hao Lu) 查詢紙本館藏

畢業系所

生命科學系

論文名稱

巨噬細胞參與癌症相關的發炎與牛皮癬發炎的分子機制
(Molecular mechanisms for the involvement of macrophages in cancer-relate inflammation and psoriatic inflammation)

檔案

[Endnote RIS 格式]

[Bibtex 格式]

[相關文章]

[文章引用]

[完整記錄]

[館藏目錄]

[檢視]

[下載]

本電子論文使用權限為同意立即開放。
已達開放權限電子全文僅授權使用者為學術研究之目的，進行個人非營利性質之檢索、閱讀、列印。
請遵守中華民國著作權法之相關規定，切勿任意重製、散佈、改作、轉貼、播送，以免觸法。

摘要(中)

巨噬細胞在先天免疫中扮演薯重要的角色。它們可識別微生物病原體並引發宿主對感染的反應。巨噬細胞是主要的發炎性細胞，可以分化成M1和M2兩種不同的型態。 M1巨噬細胞會產生促炎性的細胞因子。反之，M2巨噬細胞會產生抗發炎的細胞因子。這兩種類型的巨噬細胞之間的平衡，決定了各種發炎疾病病情的進展。
因肺部的壓力與疾病，形成的巨噬細胞在肺中的累積和發炎反應，是肺癌形成的原因之一。然而，關於巨噬細胞和腫瘤細胞兩者之間相互作用，以導致腫瘤細胞發炎反應和幹細胞特性形成的分子機構，目前的研究相當有限。我們第一部份的研究，探討泛素特異性肽酶17（USP17）在肺癌中的表達，以及USP17表達量的增加，對巨噬細胞和肺癌細胞相互作用間的影响。USP17在肺癌的表達與肺癌的預後不良，巨噬細胞和發炎的標誌物的表達有相關聯性。巨噬細胞會促進腫瘤細胞中USP17的表達量上升。分析USP17蛋白的結構發現，USP17同時具有TRAF2和TRAF3兩個蛋白的結合部位。經由此一部位USP17會與TRAF2和TRAF3交互作用，並破壞TRAF2和TRAF3所形成的複合體，因而穩定這一複合體所調控的蛋白，而導致腫瘤細胞中發炎反應的上升，幹細胞特性的增加，與巨噬細胞的募集。在動物實驗中，將巨噬細胞與腫瘤細胞共同注射在小鼠中，會促進腫瘤的生長，及腫瘤細胞中USP17表達量上升。反之，利用clodronate liposomes藥物，剔除老鼠中巨噬細胞，會降低腫瘤的生長，並抑制腫瘤細胞中USP17表達量。除此之外，USP17在腫瘤細胞中的表達，會促進腫瘤生長，而且也會增加腫瘤細胞中發炎反應，和幹細胞特性相關基因的表達。這些研究結果表明，USP17驅動了巨噬細胞和腫瘤細胞兩者之間的一個正向回饋作用，導致腫瘤細胞中發炎反應與幹細胞特性增加，最終促進了腫瘤的生長。
牛皮癬是一種影響全球2%-3%人口的發炎性的皮膚疾病。在牛皮癬發病部位，不當的或過度的活化內源性類鐸受體7、8和9，己被證明是導致牛皮癬發病的原因之一。然而，目前尚未有關於巨噬細胞的分化，是否在內源性類鐸受體活化所引起的牛皮癬發炎反應中，扮演角色的相關研究。因此，第二部份的研究，探討類鐸受體7-9在牛皮癬致病過程中，巨噬細胞的功能與作用機制。經由GEO資料庫中臨床數據的分析發現，比起正常人組織，在牛皮癬患者組織中，巨噬細胞標誌物與發炎的細胞因子都有明顯較高的表達。在動物實驗中，剔除小鼠的巨噬細胞，可抑制類鐸受體7促進劑IMQ所誘發的牛皮癬。在牛皮癬病變中，IMQ會誘導M1巨噬細胞相關特徵基因與細胞因子的表達。此外，類鐸受體7促進劑的刺激會在牛皮癬的病變中提高M1/M2巨噬細胞的比率。外源性與內源性的類鐸受體7-9配體會活化M1巨噬細胞的分化。M1巨噬細胞比起M2巨噬細胞能表現更高水平的發炎性細胞因子與類鐸受體7-9。這些結果說明，類鐸受體7-9的活化可使巨噬細胞更能夠增強因牛皮癬病變所產生的發炎反應，結果更加劇發炎反應的作用。這些結果也建議，阻斷M1巨噬細胞的分化，可能是抑制由類鐸受體活化而導致牛皮癬的發炎反應的一個方法。

摘要(英)

Macrophages play important role in innate immunity. They recognize microbial pathogens and initiate host responses to infections. Macrophage is a major inflammatory cell type that can be differentiated into M1 and M2 phenotypes. M1 macrophages produce pro-inflammatory cytokines. In contrast M2 macrophages produce anti-inflammatory cytokines. The balance between these two types of macrophages determines the progression of various inflammatory diseases.
Macrophage accumulation and inflammation in the lung owing to stresses and diseases is a cause of lung cancer development. However, molecular mechanisms underlying the interaction between macrophages and cancer cells, which drive inflammation and stemness in cancers, are poorly understood. In the first part of study, we investigated the expression of ubiquitin-specific peptidase 17 (USP17) in lung cancers, and role of elevated USP17 in the interaction between macrophages and lung cancer cells. USP17 expression in lung cancers was associated with poor prognosis, macrophage, inflammatory marker expressions. Macrophages promoted USP17 expression in cancer cells. TNFR-associated factor (TRAF) 2- and TRAF3-binding motifs were identified in USP17, through which it interacted with and disrupted the TRAF2/TRAF3 complex. This stabilized its client proteins, enhanced inflammation and stemness in cancer cells, and promoted macrophage recruitment. In different animal studies, co-injection of macrophages with cancer cells promoted USP17 expression in tumors and tumor growth. Conversely, depletion of macrophages in host animals by clodronate liposomes reduced USP17 expression and tumor growth. In addition, overexpression of USP17 in cancer cells promoted tumor growth and inflammation-associated and stemness-associated gene expressions in tumors. These results suggested that USP17 drives a positive-feedback interaction between macrophages and cancer cells to enhance inflammation and stemness in cancer cells, and promotes lung cancer growth.
Psoriasis is a chronic inflammatory skin disorder that affects ~2%–3% of the worldwide population. Inappropriate and excessive activation of endosomal Toll-like receptors 7, 8, and 9 (TLRs 7–9) at the psoriatic site has been shown to play a pathogenic role in the onset of psoriasis. However, whether macrophage polarization plays a role in psoriatic inflammation activated by endosomal TLRs has not been investigated. In the second part of study, we investigated the function and mechanism of macrophages related to the pathogenic role of TLRs 7–9 in the progression of psoriasis. Analysis of clinical data in database revealed significantly increased expression of macrophage markers and inflammatory cytokines in psoriatic tissues over those in normal tissues. In animal studies, depletion of macrophages in mice ameliorated imiquimod, a TLR 7 agonist-induced psoriatic response. Imiquimod induced expression of genes and cytokines that are signature of M1 macrophage in the psoriatic lesions. In addition, treatment with this TLR 7 agonist shifted macrophages in the psoriatic lesions to a higher M1/M2 ratio. Both of the exogenous and endogenous TLR 7–9 ligands activated M1 macrophage polarization. M1 macrophages expressed higher levels of pro-inflammatory cytokines and TLRs 7–9 than M2 macrophages. These results suggest that by rendering macrophages into a more inflammatory status and capable of response to their ligands in the psoriatic sites, TLR 7–9 activation drives them to participate in endosomal TLR-activated psoriatic inflammation, resulting in an amplified inflammatory response. Our results also suggest that blocking M1 macrophage polarization could be a strategy which enables inhibition of psoriatic inflammation activated by these TLRs.

關鍵字(中)

★ 泛素特異性肽酶17
★ 巨噬細胞
★ 發炎反應
★ 肺癌
★ 牛皮癬

關鍵字(英)

★ ubiquitin-specific peptidase 17 (USP17)
★ macrophage
★ inflammation
★ Lung cancer
★ Psoriasis

論文目次

Declaration i
中文摘要 ii
英文摘要 iv
Acknowledgments vi Table of Contents vii
List of Table xi
List of Figure xii
Explanation of symbols xviii

Chapter 1: USP17 mediates macrophage promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 comple formation

1-1 Introduction 2
1-2 Materials and methods 5
1-2-1 Bioinformatics analysis 5
1-2-2 Reagents and antibodies 5
1-2-3 Cell lines and cell culture 6
1-2-4 Plasmid construction 6
1-2-5 Lentiviral expression vector construction, infection, and stable cell lines 6
1-2-6 Transfection and luciferase-reporter analysis 7
1-2-7 Reverse-transcription and real-time quantitative PCR analyses 7
1-2-8 Immunoblotting and co-immunoprecipitation analysis 7
1-2-9 Ubiquitination assays 8
1-2-10 Polarization of macrophages 9
1-2-11 Macrophage recruitment analysis 9
1-2-12 Anchorage-independent growth 9
1-2-13 Cell proliferation assay 10
1-2-14 Sphere-formation assay 10
1-2-15 Animal models of cancer 10
1-2-16 Statistical analysis 11
1-3 Results 12
1-3-1 High USP17 expression correlate with inflammatory and macrophage marker expressions, and poor prognosis in lung cancer. 12
1-3-2 Induction of USP17 expression in cancer cells by macrophages. 13
1-3-3 USP17 promotes intrinsic inflammation and stimuli activated inflammatory responses in lung cancer cells. 14
1-3-4 USP17 promotes stemness and transformation ability of cancer cells. 15
1-3-5 USP17 expression in cancer cells promotes macrophage recruitment and cytokine production by macrophages. 16
1-3-6 USP17contains binding motifs that allow it to interact with and disrupt the protein-degradation ability of the TRAF2/TRAF3 complex. 17
1-3-7 USP17 drives a positive-feedback interaction between macrophages and cancer cells to promote tumor growth. 18
1-4 Discussion 20
1-5 References 24

Chapter 2: Involvement of M1 Macrophage Polarization in Endosomal Toll-
Like Receptors Activated Psoriatic Inflammation

2-1 Introduction 79
2-2 Materials and methods 82
2-2.1 Reagents and Antibodies 82
2-2.2 Bioinformatics Analysis of Gene Expression in Patients with Psoriasis. 82
2-2.3 Animal studies 82
2-2.4 Cell culture and bone marrow-derived macrophage production. 82
2-2.5 Activation and polarization of the monocytic THP-1 cells into M1 and M2 macrophages. 83
2-2.6 Analysis using real-time quantitative polymerase chain reaction. 83
2-2.7 Cytotoxicity assay 84
2-2.8 Enzyme-linked immunosorbent assay for cytokine production. 84
2-2.9 Macrophage depletion In Vivo by clodronate-containing liposomes. 84
2-2-10 Flow cytometric analysis 85
2-2-11 Animal model of psoriatic inflammation 85
2-2-12 Statistical analyses 86
2-3 Results 87
2-3-1 Accumulation of macrophages and inflammation in the psoriatic lesions of patients. 87
2-3-2 Involvement of macrophages and macrophage polarization in imiquimod-activated psoriatic inflammation. 87
2-3-3 Induction of M1 macrophage polarization by TLR 7–9 ligands 94
2-3-4 Induction of M1 macrophage polarization and cytokine Production by endogenous TLR 7–9 ligands 89
2-3-5 M1 Macrophages contain higher expression levels of inflammatory cytokines and TLRs 7–9 than M2 Macrophages 91
2-3-6 Using inhibitors to block TLR 7- to TLR 9-activated M1 macrophage polarization and cytokine production 92
2-3-7 Role of M1 macrophage polarization in endosomal Toll-like receptor-activated psoriatic inflammation. 92
2-4 Discussion 94
2-5 References 98

參考文獻

Burrows JF., Kelvin AA, McFarlane C, Burden RE, McGrattan MJ, De la Vega M, et al. 2009. USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity. J Biol Chem. 284:9587–95.

Borbely G., Haldosen LA, Dahlman-Wright K, Zhao C. Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells. 2015. Oncotarget. 6:33623–35.

Bolli E., Movahedi K, Laoui D, Van Ginderachter JA. Novel insights in the regulation and function of macrophages in the tumor microenvironment. 2017. Curr Opin Oncol. 29:55–61.

Chen J., Chen ZJ. Regulation of NF-kappaB by ubiquitination. 2013. Curr Opin Immunol. 25:4–12.

Chen R., Zhang L, Zhong B, Tan B, Liu Y, Shu HB, et al. The ubiquitin-specific protease 17 is involved in virus-triggered type I IFN signaling. 2010. Cell Res. 20:802–11.

Conway EM, Pikor LA, Kung SH, Hamilton MJ, Lam S, Lam WL, et al. Macrophages, inflammation, and lung cancer. 2016. Am J Respir Crit Care Med. 193:116–30.

Doedens AL., Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. 2010. Cancer Res. 70:7465–75.

De la Vega M., Kelvin AA, Dunican DJ, McFarlane C, Burrows JF, Jaworski J, et al. The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility. 2011. Nat Commun. 2:259.

Elinav E., Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. 2013. Nat Rev Cancer. 13:759–71.

Farshi P., Deshmukh RR, Nwankwo JO, Arkwright RT, Cvek B, Liu J, et al. Deubiquitinases (DUBs) and DUB inhibitors: a patent review. 2015. Expert Opin Ther Pat. 25:1191–208.

Guasparri I., Wu H, Cesarman E. The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling. 2006. EMBO Rep. 7:114–9.

Győrffy B., Surowiak P, Budczies J, Lánczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. 2013. PLoS ONE. 8:e82241.

Goswami KK., Ghosh T, Ghosh S, Sarkar M, Bose A, Baral R, et al. Tumor promoting role of anti-tumor macrophages in tumor microenvironment. 2017. Cell Immunol. 316:1–10.

Herbst RS., Heymach JV, Lippman SM. Lung cancer. 2008. N Engl J Med. 359:1367–80.

Hanahan D., Weinberg RA. Hallmarks of cancer: the next generation. 2011. Cell. 144:646–74.

Houghton AM. Mechanistic links between COPD and lung cancer. 2013. Nat Rev Cancer. 13:233–45.

Hoesel B, Schmid JA. The complexity of NF-kappaB signaling in inflammation and cancer. 2013. Mol Cancer.12:86.

Jin J, Xiao Y, Hu H, Zou Q, Li Y, Gao Y, et al. Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages. 2015. Nat Commun. 6:5930.

Korkaya H., Liu S, Wicha MS. Regulation of cancer stem cells by cytokine networks: attacking cancer’s inflammatory roots. 2011. Clin Cancer Res. 17:6125–9.

Lim KH., Ramakrishna S, Baek KH. Molecular mechanisms and functions of cytokine-inducible deubiquitinating enzymes. 2013. Cytokine Growth Factor Rev. 24:427–31.

Lanczky A., Nagy A, Bottai G, Munkacsy G, Paladini L, Szabo A, et al. miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2,178 breast cancer patients. 2016. Breast Cancer Res Treat. 160:439–46.

Liu T., Yu J, Deng M, Yin Y, Zhang H, Luo K, et al. CDK4/6- dependent activation of DUB3 regulates cancer metastasis through SNAIL1. 2017. Nat Commun. 8:13923.

Torre LA., Siegel RL, Jemal A. Lung cancer statistics. 2016. Adv Exp Med Biol. 893:1–19.

Sica A., Allavena P, Mantovani A. Cancer related inflammation: the macrophage connection. 2008. Cancer Lett. 267:204–15.

Sainz B Jr., Carron E, Vallespinos M, Machado HL. Cancer stem cells and macrophages: implications in tumor biology and therapeutic strategies. 2016. Mediat Inflamm. 2016:9012369.

Martinez FO., Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. 2006. J Immunol. 177:7303–11.

McFarlane C., Kelvin AA, de la Vega M, Govender U, Scott CJ, Burrows JF, et al. The deubiquitinating enzyme USP17 is highly expressed in tumor biopsies, is cell cycle regulated, and is required for G1-S progression. 2006. Cancer Res. 70:3329–39.

Magee JA., Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. 2012. Cancer Cell. 21:283–96.

McFarlane C., McFarlane S, Paul I, Arthur K, Scheaff M, Kerr K, et al. The deubiquitinating enzyme USP17 is associated with nonsmall cell lung cancer (NSCLC) recurrence and metastasis. 2013. Oncotarget. 4:1836–43.

MacDonagh L., Gray SG, Breen E, Cuffe S, Finn SP, O’Byrne KJ, et al. Lung cancer stem cells: The root of resistance. 2016. Cancer Lett. 372:147–56.

Noy R., Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. 2014. Immunity. 41:49–61.

Ni Y., Tao L, Chen C, Song H, Li Z, Gao Y, et al. The Deubiquitinase USP17 regulates the stability and nuclear function of IL-33. 2015. Int J Mol Sci. 16:27956–66.

Popovic D., El-Shami KM, Vadai E, Feldman M, Tzehoval E, Eisenbach L. Antimetastatic vaccination against Lewis lung carcinoma with autologous tumor cells modified to express murine interleukin 12. 1998. Clin Exp Metastasis. 16:623–32.

Pereg Y., Liu BY, O’Rourke KM, Sagolla M, Dey A, Komuves L, et al. Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A. 2010. Nat Cell Biol. 12:400–6.

Pal A., Donato NJ. Ubiquitin-specific proteases as therapeutic targets for the treatment of breast cancer. 2014. Breast Cancer Res. 16:461.

Quatromoni JG., Eruslanov E. Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. 2012. Am J Transl Res. 4:376–89.

Ramakrishna S., Suresh B, Lee EJ, Lee HJ, Ahn WS, Baek KH, et al. Lys-63-specific deubiquitination of SDS3 by USP17 regulates HDAC activity. 2011. J Biol Chem. 286:10505–14.

Ramakrishna S., Suresh B, Bae SM, Ahn WS, Lim KH, Baek KH, et al. Hyaluronan binding motifs of USP17 and SDS3 exhibit antitumor activity. 2012. PLoS ONE. 7:e37772.

Ramakrishna S., Suresh B, Baek KH. Biological functions of hyaluronan and cytokine-inducible deubiquitinating enzymes. 2015. Biochim Biophys Acta. 1855:83–91.

Shigdar S., Li Y, Bhattacharya S, O’Connor M, Pu C, Lin J, et al. Inflammation and cancer stem cells. 2014. Cancer Lett. 345:271–8.

Suresh R., Ali S, Ahmad A, Philip PA, Sarkar FH. The role of cancer stem cells in recurrent and drug-resistant lung cancer. 2016. Adv Exp Med Biol. 890:57–74.

Suarez-Carmona M., Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. 2017. Mol Oncol. 11:805–23.

Sica A., Porta C, Amadori A, Pasto A. Tumor-associated myeloid cells as guiding forces of cancer cell stemness. 2017. Cancer Immunol Immunother. 66:1025–36.

Todoric J., Antonucci L, Karin M. Targeting inflammation in cancer prevention and therapy. 2016. Cancer Prev Res. 9:895–905.

Visvader JE., Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. 2008. Nat Rev Cancer. 8:755–68.

Vallabhapurapu S., Matsuzawa A, Zhang W, Tseng PH, Keats JJ, Wang H, et al. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. 2008. Nat Immunol. 9:1364–70.

Verstrepen L., Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R, et al. TLR-4, IL-1R and TNF-R signaling to NFkappaB: variations on a common theme. 2008. Cell Mol Life Sci. 65:2964–78.

Valavanidis A., Vlachogianni T, Fiotakis K, Loridas S. Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms. 2013. Int J Environ Res Public Health. 10:3886–907.

Won M., Byun HS, Park KA, Hur GM. Post-translational control of NF-kappaB signaling by ubiquitination. 2016. Arch Pharm Res. 39:1075–84.

Wu Y., Wang Y, Lin Y, Liu Y, Wang Y, Jia J, et al. Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting snail1 degradation. 2017. Nat Commun. 8:14228.

Xie P. TRAF molecules in cell signaling and in human diseases. 2013. J Mol Signal. 8:7.

Ye H., Park YC, Kreishman M, Kieff E, Wu H. The structural basis for the recognition of diverse receptor sequences by TRAF2. 1999. Mol Cell. 4:321–30.

Yang XD., Sun SC. Targeting signaling factors for degradation, an emerging mechanism for TRAF functions. 2015. Immunol Rev. 266:56–71.

Yeh DW., Chen YS, Lai CY, Liu YL, Lu CH, Lo JF, et al. Downregulation of COMMD1 by miR-205 promotes a positive feedback loop for amplifying inflammatory- and stemness-associated properties of cancer cells. 2016. Cell Death Differ. 23:841–52.

Yeh DW., Huang LR, Chen YW, Huang CF, Chuang TH. Interplay between inflammation and stemness in cancer cells: the role of tolllike receptor signaling. 2016. J Immunol Res. 4368101.

Zarnegar BJ., Wang Y, Mahoney DJ, Dempsey PW, Cheung HH, He J, et al. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. 2008. Nat Immunol. 9:1371–8.

Zhang S., Yuan J, Zheng R. Suppression of ubiquitin-specific peptidase 17 (USP17) inhibits tumorigenesis and invasion in nonsmall cell lung cancer Cells. 2016. Oncol Res. 24:263269.

A AG, Tyring SK, Rosen T. Beyond a decade of 5% imiquimod topical therapy. 2009. J Drugs Dermatol. 8: 467-474.

Balak DM, van Doorn MB, Arbeit RD, Rijneveld R, Klaassen E, Sullivan T et al. IMO-8400, a toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis. 2007. Clin Immunol.174: 63-72.

Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. 2007. J Leukoc Biol. 81: 1-5.

Biswas SK, Chittezhath M, Shalova IN, Lim JY. Macrophage polarization and plasticity in health and disease. 2012. Immunol Res. 53: 11-24.

Blasius AL, Beutler B. Intracellular toll-like receptors. 2010. Immunity. 32: 305-315.

Chamilos G, Gregorio J, Meller S, Lande R, Kontoyiannis DP, Modlin RL et al. Cytosolic sensing of extracellular self-DNA transported into monocytes by the antimicrobial peptide LL37. 2012. Blood. 120: 3699-3707.

Chen T, Fu LX, Zhang LW, Yin B, Zhou PM, Cao N et al. Paeoniflorin suppresses inflammatory response in imiquimod-induced psoriasis-like mice and peripheral blood mononuclear cells (PBMCs) from psoriasis patients. 2016. Can J Physiol Pharmacol. 94: 888-894.

Christophers E. Psoriasis--epidemiology and clinical spectrum. 2001. Clin Exp Dermatol. 26: 314-320.

Chuang T, Ulevitch RJ. Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. 2001. Biochim Biophys Acta. 1518: 157-161.

Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. 2010. Cancer Res. 70: 7465-7475.

Eberle FC, Bruck J, Holstein J, Hirahara K, Ghoreschi K. Recent advances in understanding psoriasis. 2016. F1000Res. 5.

Fanti PA, Dika E, Vaccari S, Miscial C, Varotti C. Generalized psoriasis induced by topical treatment of actinic keratosis with imiquimod. 2006. Int J Dermatol. 45: 1464-1465.

Funes SC, Rios M, Escobar-Vera J, Kalergis AM. Implications of macrophage polarization in autoimmunity. 2018. Immunology. 186-195.

Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. 2009. J Exp Med. 206: 1983-1994.

Gilliet M, Conrad C, Geiges M, Cozzio A, Thurlimann W, Burg G et al. Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. 2004. Arch Dermatol. 140: 1490-1495.

Herwald H, Egesten A. On PAMPs and DAMPs. 2016. J Innate Immun. 8: 427-428.

Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T et al. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. 2002. J Immunol. 168: 4531-4537.

Huang SW, Chen YJ, Wang ST, Ho LW, Kao JK, Narita M et al. Azithromycin impairs TLR7 signaling in dendritic cells and improves the severity of imiquimod-induced psoriasis-like skin inflammation in mice. 2016. J Dermatol Sci. 84: 59-70.

Huen AO, Rook AH. Toll receptor agonist therapy of skin cancer and cutaneous T-cell lymphoma. 2014. Curr Opin Oncol. 26: 237-244.

Imler JL, Hoffmann JA. Toll receptors in innate immunity. 2001. Trends Cell Biol. 11: 304-311.

Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. 2014. Nat Immunol.5: 987-995.

Karuppagounder V, Arumugam S, Thandavarayan RA, Sreedhar R, Giridharan VV, Pitchaimani V et al. Naringenin ameliorates skin inflammation and accelerates phenotypic reprogramming from M1 to M2 macrophage polarization in atopic dermatitis NC/Nga mouse model. 2016. Exp Dermatol. 25: 404-407.

Kay E, Scotland RS, Whiteford JR. Toll-like receptors: Role in inflammation and therapeutic potential. 2014. Biofactors. 40: 284-294.

Kim HJ, Kim SH, Je JH, Shin DY, Kim DS, Lee MG. Increased expression of Toll-like receptors 3, 7, 8 and 9 in peripheral blood mononuclear cells in patients with psoriasis. 2016. Exp Dermatol. 25: 485-487.

Kircik LH, Del Rosso JQ. Anti-TNF agents for the treatment of psoriasis. 2009. J Drugs Dermatol. 8: 546-559.

Kusuba N, Kitoh A, Dainichi T, Honda T, Otsuka A, Egawa G et al. Inhibition of IL-17-committed T cells in a murine psoriasis model by a vitamin D analogue. 2018. J Allergy Clin Immunol. 141: 972-981 e910.

Lafferty EI, Qureshi ST, Schnare M. The role of toll-like receptors in acute and chronic lung inflammation. 2010. J Inflamm (Lond). 7: 57.

Lai CY, Yeh DW, Lu CH, Liu YL, Huang LR, Kao CY et al. Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7-9. 2015. J Immunol. 195: 3912-3921.

Lai CY, Su YW, Lin KI, Hsu LC, Chuang TH. Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation. 2017. J Immunol Res. 2017: 7807313.

Lee SM, Yip TF, Yan S, Jin DY, Wei HL, Guo RT et al. Recognition of Double-Stranded RNA and Regulation of Interferon Pathway by Toll-Like Receptor 10. 2018. Front Immunol. 9: 516.

Liu J, Xu C, Hsu LC, Luo Y, Xiang R, Chuang TH. A five-amino-acid motif in the undefined region of the TLR8 ectodomain is required for species-specific ligand recognition. 2010. Mol Immunol. 47: 1083-1090.

Liu YC, Zou XB, Chai YF, Yao YM. Macrophage polarization in inflammatory diseases.2014. Int J Biol Sci. 10: 520-529.

Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. 2007. Nature. 445: 866-873.

Lowes MA, Suarez-Farinas M, Krueger JG. Immunology of psoriasis.2014. Annu Rev Immunol. 32: 227-255.

Mahil SK, Capon F, Barker JN. Update on psoriasis immunopathogenesis and targeted immunotherapy. 2016. Semin Immunopathol. 38: 11-27.

Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. 2006. Nat Rev Immunol. 6: 823-835.

Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. 2006. J Immunol. 177: 7303-7311.

McGettrick AF, O′Neill LA. Localisation and trafficking of Toll-like receptors: an important mode of regulation. 2010. Curr Opin Immunol. 22: 20-27.

Medzhitov R, Janeway C, Jr. The Toll receptor family and microbial recognition. 2000. Trends Microbiol. 8: 452-456.

Morimura S, Oka T, Sugaya M, Sato S. CX3CR1 deficiency attenuates imiquimod-induced psoriasis-like skin inflammation with decreased M1 macrophages. 2016. J Dermatol Sci. 82: 175-188.

Morizane S, Yamasaki K, Muhleisen B, Kotol PF, Murakami M, Aoyama Y et al. Cathelicidin antimicrobial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands. 2012. J Invest Dermatol. 132: 135-143.

Motwani MP, Gilroy DW. Macrophage development and polarization in chronic inflammation. 2015. Semin Immunol. 27: 257-266.

Muraille E, Leo O, Moser M. TH1/TH2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism? 2014. Front Immunol. 5: 603.

Murray PJ. Macrophage Polarization. 2017. Annu Rev Physiol. 79: 541-566.

Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. 2009. Nat Genet. 41: 199-204.

Parisi L, Gini E, Baci D, Tremolati M, Fanuli M, Bassani B et al. Macrophage Polarization in Chronic Inflammatory Diseases: Killers or Builders? 2018. J Immunol Res. 2018: 8917804.

Patel U, Mark NM, Machler BC, Levine VJ. Imiquimod 5% cream induced psoriasis: a case report, summary of the literature and mechanism. 2011. Br J Dermatol. 164: 670-672.

Perera GK, Di Meglio P, Nestle FO. Psoriasis. 2012. Annu Rev Pathol. 7: 385-422.

Rabeony H, Pohin M, Vasseur P, Petit-Paris I, Jegou JF, Favot L et al. IMQ-induced skin inflammation in mice is dependent on IL-1R1 and MyD88 signaling but independent of the NLRP3 inflammasome. 2015. Eur J Immunol. 45: 2847-2857.

Saadeh D, Kurban M, Abbas O. Update on the role of plasmacytoid dendritic cells in inflammatory/autoimmune skin diseases. 2016. Exp Dermatol. 25: 415-421.

Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F et al. Macrophage plasticity, polarization, and function in health and disease. 2018. J Cell Physiol. 233: 6425-6440.

Shibata S, Tada Y, Asano Y, Yanaba K, Sugaya M, Kadono T et al. IL-27 activates Th1-mediated responses in imiquimod-induced psoriasis-like skin lesions. 2013. J Invest Dermatol. 133: 479-488.

Sica A, Erreni M, Allavena P, Porta C. Macrophage polarization in pathology. 2015. Cell Mol Life Sci. 72: 4111-4126.

Suarez-Farinas M, Arbeit R, Jiang W, Ortenzio FS, Sullivan T, Krueger JG. Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation. 2013. PLoS One. 8: e84634.

Tsan MF, Gao B. Endogenous ligands of Toll-like receptors. 2004. J Leukoc Biol. 76: 514-519.

Ueyama A, Yamamoto M, Tsujii K, Furue Y, Imura C, Shichijo M et al. Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: a role for interferon-alpha in dendritic cell activation by imiquimod. 2014. J Dermatol. 41: 135-143.

Walter A, Schafer M, Cecconi V, Matter C, Urosevic-Maiwald M, Belloni B et al. Aldara activates TLR7-independent immune defence. 2013. Nat Commun. 4: 1560.

Wohn C, Ober-Blobaum JL, Haak S, Pantelyushin S, Cheong C, Zahner SP et al. Langerin(neg) conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice. 2013. Proc Natl Acad Sci U S A. 110: 10723-10728.

Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. 2002. J Immunol. 168: 554-561.

Zhang J, Lin Y, Li C, Zhang X, Cheng L, Dai L et al. IL-35 Decelerates the Inflammatory Process by Regulating Inflammatory Cytokine Secretion and M1/M2 Macrophage Ratio in Psoriasis. 2016. J Immunol. 197: 2131-2144.

Zhou D, Huang C, Lin Z, Zhan S, Kong L, Fang C et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. 2014. Cell Signal. 26: 192-197.

指導教授

金秀蓮莊宗顯(Shin-Lian Catherine Jin Tsung-Hsien Chuang))

審核日期

2019-7-24

推文