在多細胞生物中，先天性免疫是宿主抵禦病原體的第一道防線。表觀遺傳學在調控先天免疫中扮演重要的角色。我們未發表的實驗結果顯示異染色質形成會活化先天免疫進而增加果蠅抵抗綠膿桿菌 PA14的感染。然而異染色質在血球細胞中如何調控吞噬作用及先天免疫反應進而抵抗PA14感染的分子機制尚未清楚。藉由研究相似於哺乳類巨噬細胞的果蠅血球細胞，我們探討血球細胞的異染色質如何調控PA14感染所引發的先天性免疫反應。首先我們發現血球細胞對於果蠅抵抗綠膿桿菌 PA14的感染扮演必要的角色。血球細胞藉由吞噬作用及活化脂肪細胞釋放抗微生物肽，以清除PA14進而增加宿主的存活率。重要的是，異染色質的形成參與血球細胞表觀基因組的重新編程進而促進PA14抗菌反應。血球細胞的異染色質藉由跨組織的方式促進脂肪細胞的免疫反應，並且會在PA14的感染初期時促進Dorsal蛋白質進入細胞核內。令人驚訝的是，血球細胞的異染色質增加會降低造血中心的血球細胞數量。綜上所述，這些結果指出一種新的調控先天免疫之表觀遺傳機制，此中異染色質的形成促進巨噬細胞介導的先天免疫反應，並為傳染性疾病的預防和治療方式提供更進一步的發展。

In multicellular organisms, the innate immune system is the first line of defense against pathogen infection. Epigenetics plays an important role in regulating innate immunity. Our unpublished study has found that heterochromatin formation activates innate immune pathways against the human pathogen Pseudomonas aeruginosa PA14 in Drosophila. However, molecular mechanisms by which heterochromation formation regulates phagocytosis and innate immune responses mediated by macrophages against PA14 remain elusive. Here by studying heterochromatin-mediated innate immunity by hemocytes, analogous to mammalian macrophages, against PA14 infection in Drosophila, we first found that hemocytes are essential for survival of Drosophila against P. aeruginosa PA14 infection. Moreover, hemocytes facilitate PA14 clearance through phagocytosis and activating release of AMPs. Importantly, heterochromatin formation participates in reprogramming of hemocyte epigenomes upon PA14 infection to promote antibacterial defense. Hemocyte-specific heterochromatin formation activates cross-tissue immune responses in fat body cells, and promotes Dorsal nuclear translocation upon early PA14 infection. Surprisingly, we found that increased heterochromatin formation in hemocytes decreases hemocyte number in the hematopoietic hubs. Altogether, these results reveal a novel epigenetic mechanism by which heterochromatin formation promotes macrophage-mediated innate immune responses and provide deeper insights into prevention and therapeutics against infectious diseases.

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