MiR-23a Regulates Skin Langerhans Cell Phagocytosis and Inflammation-Induced Langerhans Cell Repopulation.
MiR-23a Regulates Skin Langerhans Cell Phagocytosis and Inflammation-Induced Langerhans Cell Repopulation.
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作者：
调控表观遗传信号在皮肤朗格汉斯细胞(LCS)个体发育、维持和功能中介导动态平衡免疫反应在很大程度上尚不确定。在这里，我们证明了表观遗传调节因子miR-23a不仅在LC抗原摄取中起着不可或缺的作用，而且在炎症条件下对骨髓源性LC的再生也是至关重要的。在此过程中，miR-23a可能通过介导吞噬和吞噬作用调节LC吞噬功能，也可能通过靶向Fas和Bcl2家族促凋亡分子来调节LC的再增殖。相反，miR-23a没有证明在LC的发育和出生后的动态平衡中起任何作用。因此，miR-23a在LC中的上下文相关调节作用可能代表了在稳态和炎症诱导的再生长过程中整合转化生长因子-β和PU.1介导的调节的表外遗传层。郎格汉斯细胞(LCS)是一种皮肤驻留的巨噬细胞，其作用类似于树突状细胞，控制皮肤的获得性免疫和免疫耐受，在许多皮肤病的发生发展中起关键作用。虽然已知转化生长因子-β及其下游信号通路控制LC生物学的许多方面，但对LC个体发生、维持和功能过程中协调细胞信号的表观遗传信号知之甚少。我们以前在完全miRNA缺失的小鼠模型中的研究表明，miRNAs在胚胎LC发育和出生后LC动态平衡中起关键作用；然而，调节LC的特异性miRNA(S)仍然未知。MiR-23a是miR-23a-27a-24-2簇的第一个成员，miR-23a-27a-24-2簇是PU.1和TGF-b的直接下游靶点，它们调节髓系和淋巴系命运的决定。因此，我们使用髓系特异性miR-23a缺失小鼠模型来探讨miR-23a是否以及如何影响皮肤中LC的个体发育和功能。我们观察到miR-23a在LC抗原摄取和炎症诱导的LC表皮再生中起着不可或缺的作用；然而，缺失miR23a的细胞并不影响胚胎LC的发育和出生后的动态平衡。我们的结果表明，miR-23a通过靶向调节吞噬和吞噬作用的分子来控制LC的吞噬作用，而miR-23a通过靶向Fas和Bcl-2家族促凋亡分子来促进骨髓源性LC的动态平衡，这些LC在炎症损伤后重新填充皮肤。总体而言，miR-23a在LCS中的上下文相关调节作用代表了一个额外的表观遗传层，它在稳态和炎症诱导的再繁殖过程中结合了转化生长因子-b和PU.1介导的调节。
Controlling epigenetic signals for mediating the homeostatic immune response in skin-residing Langerhans cells (LCs) ontogeny, maintenance, and function are largely not determined. Here, we demonstrated that the epigenetic regulator miR-23a not only plays an indispensable role for LC antigen uptake but is also crucial for bone marrow-derived LC repopulation during the inflammatory condition. During this process, miR-23a may regulate LC phagocytosis by mediating efferocytosis and endocytosis-mediated targets as well as LCs repopulation via targeting Fas and Bcl-2 family proapoptotic molecules. Instead, miR-23a did not demonstrate playing any role in LC development and postnatal homeostasis. Thus, the context-dependent regulatory role of miR-23a in LCs may represent an extra-epigenetic layer for incorporating TGF-β and PU.1-mediated regulation during steady-state and inflammation-induced repopulation. Langerhans cells (LCs) are skin-resident macrophage that act similarly to dendritic cells for controlling adaptive immunity and immune tolerance in the skin, and they are key players in the development of numerous skin diseases. While TGF-β and related downstream signaling pathways are known to control numerous aspects of LC biology, little is known about the epigenetic signals that coordinate cell signaling during LC ontogeny, maintenance, and function. Our previous studies in a total miRNA deletion mouse model showed that miRNAs are critically involved in embryonic LC development and postnatal LC homeostasis; however, the specific miRNA(s) that regulate LCs remain unknown. miR-23a is the first member of the miR-23a-27a-24-2 cluster, a direct downstream target of PU.1 and TGF-b, which regulate the determination of myeloid versus lymphoid fates. Therefore, we used a myeloid-specific miR-23a deletion mouse model to explore whether and how miR-23a affects LC ontogeny and function in the skin. We observed the indispensable role of miR-23a in LC antigen uptake and inflammation-induced LC epidermal repopulation; however, embryonic LC development and postnatal homeostasis were not affected by cells lacking miR23a. Our results suggest that miR-23a controls LC phagocytosis by targeting molecules that regulate efferocytosis and endocytosis, whereas miR-23a promotes homeostasis in bone marrow-derived LCs that repopulate the skin after inflammatory insult by targeting Fas and Bcl-2 family proapoptotic molecules. Collectively, the context-dependent regulatory role of miR-23a in LCs represents an extra-epigenetic layer that incorporates TGF-b- and PU.1-mediated regulation during steady-state and inflammation-induced repopulation.
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影响因子：
37.3
作者：
Chhabra R;Dubey R;Saini N
通讯作者：
Saini N
DOI：
10.1084/jem.20120340
发表时间：
2012-06-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hoeffel G;Wang Y;Greter M;See P;Teo P;Malleret B;Leboeuf M;Low D;Oller G;Almeida F;Choy SH;Grisotto M;Renia L;Conway SJ;Stanley ER;Chan JK;Ng LG;Samokhvalov IM;Merad M;Ginhoux F
通讯作者：
Ginhoux F
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
2.6
作者：
Kong, Kimi Y.;Owens, Kristin S.;Rogers, Jason H.;Mullenix, Jason;Velu, Chinavenmeni S.;Grimes, H. Leighton;Dahl, Richard
通讯作者：
Dahl, Richard
影响因子：
3.7
作者：
Lillis AP;Muratoglu SC;Au DT;Migliorini M;Lee MJ;Fried SK;Mikhailenko I;Strickland DK
通讯作者：
Strickland DK