Macrophage-dependent neutrophil recruitment is impaired under conditions of increased intestinal permeability in JAM-A-deficient mice.,Mucosal Immunology

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Macrophage-dependent neutrophil recruitment is impaired under conditions of increased intestinal permeability in JAM-A-deficient mice.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2019-02-11 , DOI: 10.1038/s41385-019-0143-7
Anny-Claude Luissint ₁ , Holly C Williams ₂ , Wooki Kim ₃ , Sven Flemming ₁ , Veronica Azcutia ₁ , Roland S Hilgarth ₁ , Monique N O' Leary ₁ , Timothy L Denning ₄ , Asma Nusrat ₁ , Charles A Parkos ₁

Affiliation

Junctional adhesion molecule-A (JAM-A) is a transmembrane glycoprotein expressed on leukocytes, endothelia, and epithelia that regulates biological processes including barrier function and immune responses. While JAM-A has been reported to facilitate tissue infiltration of leukocytes under inflammatory conditions, the contributions of leukocyte-expressed JAM-A in vivo remain unresolved. We investigated the role of leukocyte-expressed JAM-A in acute peritonitis induced by zymosan, lipopolysaccharide (LPS), or TNFα using mice with selective loss of JAM-A in myelomonocytic cells (LysM-Cre;Jam-afl/fl). Surprisingly, in LysM-Cre;Jam-afl/fl mice, loss of JAM-A did not affect neutrophil (PMN) recruitment into the peritoneum in response to zymosan, LPS, or TNFα although it was significantly reduced in Jam-aKO mice. In parallel, Jam-aKO peritoneal macrophages exhibited diminished CXCL1 chemokine production and decreased activation of NF-kB, whereas those from LysM-Cre;Jam-afl/fl mice were unaffected. Using Villin-Cre;Jam-afl/fl mice, targeted loss of JAM-A on intestinal epithelial cells resulted in increased intestinal permeability along with reduced peritoneal PMN migration as well as lower levels of CXCL1 and active NF-kB similar to that observed in Jam-aKO animals. Interestingly, in germ-free Villin-Cre;Jam-afl/fl mice, PMN recruitment was unaffected suggesting dependence on gut microbiota. Such observations highlight the functional link between a leaky gut and regulation of innate immune responses.

中文翻译：

在 JAM-A 缺陷小鼠肠道通透性增加的情况下，巨噬细胞依赖性中性粒细胞募集受损。

连接粘附分子-A (JAM-A) 是一种在白细胞、内皮细胞和上皮细胞上表达的跨膜糖蛋白，可调节包括屏障功能和免疫反应在内的生物过程。虽然已报道 JAM-A 在炎症条件下促进白细胞的组织浸润，但白细胞表达的 JAM-A 在体内的作用仍未得到解决。我们使用在骨髓单核细胞 (LysM-Cre;Jam-afl/fl) 中选择性缺失 JAM-A 的小鼠研究了白细胞表达的 JAM-A 在酵母聚糖、脂多糖 (LPS) 或 TNFα 诱导的急性腹膜炎中的作用。令人惊讶的是，在 LysM-Cre；Jam-afl/fl 小鼠中，JAM-A 的缺失并不影响嗜中性粒细胞 (PMN) 募集到腹膜以响应酵母聚糖、LPS 或 TNFα，尽管它在 Jam-aKO 小鼠中显着减少。在平行下，Jam-aKO 腹膜巨噬细胞表现出 CXCL1 趋化因子产生减少和 NF-kB 激活减少，而来自 LysM-Cre 的巨噬细胞；Jam-afl/fl 小鼠不受影响。使用 Villin-Cre；Jam-afl/fl 小鼠，肠上皮细胞上 JAM-A 的靶向缺失导致肠道通透性增加，腹膜 PMN 迁移减少以及 CXCL1 和活性 NF-kB 水平降低，类似于在Jam-aKO 动物。有趣的是，在无菌 Villin-Cre；Jam-afl/fl 小鼠中，PMN 募集未受影响，表明对肠道菌群的依赖。这些观察结果突出了肠漏症与先天免疫反应调节之间的功能联系。Jam-afl/fl 小鼠，肠上皮细胞上 JAM-A 的靶向缺失导致肠道通透性增加以及腹膜 PMN 迁移减少以及 CXCL1 和活性 NF-kB 水平降低，类似于在 Jam-aKO 动物中观察到的情况。有趣的是，在无菌 Villin-Cre；Jam-afl/fl 小鼠中，PMN 募集未受影响，表明对肠道菌群的依赖。这些观察结果突出了肠漏症与先天免疫反应调节之间的功能联系。Jam-afl/fl 小鼠，肠上皮细胞上 JAM-A 的靶向缺失导致肠道通透性增加以及腹膜 PMN 迁移减少以及 CXCL1 和活性 NF-kB 水平降低，类似于在 Jam-aKO 动物中观察到的情况。有趣的是，在无菌 Villin-Cre；Jam-afl/fl 小鼠中，PMN 募集未受影响，表明对肠道菌群的依赖。这些观察结果突出了肠漏症与先天免疫反应调节之间的功能联系。PMN 募集不受影响，表明对肠道菌群的依赖。这些观察结果突出了肠漏症与先天免疫反应调节之间的功能联系。PMN 募集不受影响，表明对肠道菌群的依赖。这些观察结果突出了肠漏症与先天免疫反应调节之间的功能联系。

更新日期：2019-07-05

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