在仅仅18个月的时间里使一个已有可观的贷款业务量和服务规模的公司的业务量再扩大3倍并不是一件容易的事情。策划一个能适应这种难以置信的增长速度的面向未来的网络同样是件不容易的工作。 但GMA C Commercial Mortgage公司(GMAC-CM)...在仅仅18个月的时间里使一个已有可观的贷款业务量和服务规模的公司的业务量再扩大3倍并不是一件容易的事情。策划一个能适应这种难以置信的增长速度的面向未来的网络同样是件不容易的工作。 但GMA C Commercial Mortgage公司(GMAC-CM)在这两方面都成功地做到了——借助经验丰富的管理队伍和员工发展了业务并增加了业务的种类,同时利用3Com的解决方案建立了自己的网络。展开更多
Background: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immun...Background: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regulated monocytes-to-gMacs differentiation in sepsis-induced intestinal injury.Methods: Sepsis was induced in C57BL/6 wild type (WT) mice andAtf4-knockdown (Atf4+/-) mice by cecal ligation and puncture or administration of lipopolysaccharide (LPS). Colon, peripheral blood mononuclear cells, sera, lung, liver, and mesenteric lymph nodes were collected for flow cytometry, hematoxylin and eosin staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively.Results: CD64, CD11b, Ly6C, major histocompatibility complex-II (MHC-II), CX3CR1, Ly6G, and SSC were identified as optimal primary markers for detecting the process of monocytes-to-gMacs differentiation in the colon of WT mice. Monocytes-to-gMacs differentiation was impaired in the colon during sepsis and was associated with decreased expression of ATF4 in P1 (Ly6Chi monocytes), the precursor cells of gMacs.Atf4 knockdown exacerbated the impairment of monocytes-to-gMacs differentiation in response to LPS, resulting in a significant reduction of gMacs in the colon. Furthermore, compared with WT mice,Atf4+/- mice exhibited higher pathology scores, increased expression of inflammatory factor genes (TNF-α, IL-1β), suppressed expression of CD31 and vascular endothelial-cadherin in the colon, and increased translocation of intestinal bacteria to lymph nodes and lungs following exposure to LPS. However, the aggravation of sepsis-induced intestinal injury resulting fromAtf4 knockdown was not caused by the enhanced inflammatory effect of Ly6Chi monocytes and gMacs.Conclusion: ATF4, as a novel regulator of monocytes-to-gMacs differentiation, plays a critical role in protecting mice against sepsis-induced intestinal injury, suggesting that ATF4 might be a potential therapeutic target for sepsis treatment.展开更多
文摘在仅仅18个月的时间里使一个已有可观的贷款业务量和服务规模的公司的业务量再扩大3倍并不是一件容易的事情。策划一个能适应这种难以置信的增长速度的面向未来的网络同样是件不容易的工作。 但GMA C Commercial Mortgage公司(GMAC-CM)在这两方面都成功地做到了——借助经验丰富的管理队伍和员工发展了业务并增加了业务的种类,同时利用3Com的解决方案建立了自己的网络。
基金National Natural Science Foundation of China(Nos. 82172152, 81873944, 82172154, 81971869, 82171729)Natural Science Foundation of Shanghai(No.19ZR1442500)Research Fund of Ruijin Hospital North Affiliated to Shanghai Jiao Tong University School of Medicine(No.2020ZY11)
文摘Background: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regulated monocytes-to-gMacs differentiation in sepsis-induced intestinal injury.Methods: Sepsis was induced in C57BL/6 wild type (WT) mice andAtf4-knockdown (Atf4+/-) mice by cecal ligation and puncture or administration of lipopolysaccharide (LPS). Colon, peripheral blood mononuclear cells, sera, lung, liver, and mesenteric lymph nodes were collected for flow cytometry, hematoxylin and eosin staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively.Results: CD64, CD11b, Ly6C, major histocompatibility complex-II (MHC-II), CX3CR1, Ly6G, and SSC were identified as optimal primary markers for detecting the process of monocytes-to-gMacs differentiation in the colon of WT mice. Monocytes-to-gMacs differentiation was impaired in the colon during sepsis and was associated with decreased expression of ATF4 in P1 (Ly6Chi monocytes), the precursor cells of gMacs.Atf4 knockdown exacerbated the impairment of monocytes-to-gMacs differentiation in response to LPS, resulting in a significant reduction of gMacs in the colon. Furthermore, compared with WT mice,Atf4+/- mice exhibited higher pathology scores, increased expression of inflammatory factor genes (TNF-α, IL-1β), suppressed expression of CD31 and vascular endothelial-cadherin in the colon, and increased translocation of intestinal bacteria to lymph nodes and lungs following exposure to LPS. However, the aggravation of sepsis-induced intestinal injury resulting fromAtf4 knockdown was not caused by the enhanced inflammatory effect of Ly6Chi monocytes and gMacs.Conclusion: ATF4, as a novel regulator of monocytes-to-gMacs differentiation, plays a critical role in protecting mice against sepsis-induced intestinal injury, suggesting that ATF4 might be a potential therapeutic target for sepsis treatment.
