2021-01-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/702489Siglec是一群主要表現在免疫細胞負責辨識含有唾液酸醣蛋白的受體，目前已知當其被鍵結後可以利用其細胞內的ITIM motif吸引SHP去磷酸酶，來負調控免疫細胞的活化。腫瘤細胞所分泌的唾液酸蛋白已知可以分別藉由鍵結NK細胞與中性球細胞上的Siglec-7與Siglec-9受體，來抑制其抗腫瘤效果。此外，含有唾液酸的粘蛋白(MUC1)，已知可以藉由Siglec-9受體來引起巨噬細胞趨向於表現腫瘤相關巨噬細胞的部分特性，例如增加PD-L1的表現。Siglec家族目前已知有三個成員不具有ITIM motif並可與具有ITAM motif的DAP12蛋白結合分別是Siglec-14、Siglec-15、與Siglec-16，當其被鍵結時可以傳遞正向訊號。其中Siglec-14與Siglec-5是paired receptor，它們可以辨識相同的配體但是會傳遞不同的訊號，並且已知Siglec-14在人群中具有多形性，有些人不表現Siglec-14。Siglec-14的表現曾被報導會與慢性肺阻塞病的發生成正相關，而COPD的發生與肺中出現較多的M2巨噬細胞亦呈正相關。因此，在此計畫中，我們希望探討Siglec-5/Siglec-14對於巨噬細胞極化的影響。 Sialic acid (Sia)-binding immunoglobulin-like lectins (Siglecs), a family of lectins that binds to Sia-containing carbohydrate structures (sialoglycans), predominantly expressing on immune cells and has been shown to negatively regulate cell activation via recruiting SHP phosphotases via its cytosolic ITIM motifs. Tumor-associated sialoglycans were shown to directly reduce the anti-tumor activity of NK cell and neutrophils by targeting Siglec-7 and Siglec-9 expressing on NK cells and neutrophils, respectively. In addition, sialylated mucin, MUC1 was able to induce macrophages to display a TAM-like phenotype, with increased expression of the checkpoint ligand PD-L1 through engaging the Siglec-9 expressing on macrophages. Three human activating Siglecs have been discovered so far, namely Siglec-14, Siglec-15 and Siglec-16. These activating Siglecs, unlike most of the discovered, Siglecs lack intracellular ITIMs, and instead have a charged residue in the transmembrane domain to recruit DAP12 adaptor and signal through its ITAM motifs. More interestingly, there are paired inhibitory/activating Siglec sets discovered in humans (Siglec-5/14 and Siglec-11/16), in which the Sia-binding properties of the two Siglecs are kept identical by gene conversion, but they transmit opposite intracellular signals. In addition, absence of Siglec-14 expression due to homozygosity of SIGLEC14 null allele caused by fusion of the SGILEC14 and SIGLEC5 genes generates a unique polymorphism occurring at varying frequencies based on the geographic origins of the human population. The biological impacts of this activating SIGLEC14 allele has been reported to associate with the increased frequency of acute exacerbations of chronic obstructive pulmonary disease, which is associated increased M2 macrophages in the lungs. Therefore, we aim to elucidate the impact of the paired Siglec in macrophage polarization in this sub-project.腫瘤相關巨噬細胞巨噬細胞極化發炎tumor-associated macrophagemacrophage polarizationinflammation