| 摘要: | 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。
;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. |
