Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel-CGRP-Jdp2 Axis
Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel-CGRP-Jdp2 Axis
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DOI：
10.1016/j.celrep.2017.06.002
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发表时间：
2017-06-27
期刊：
影响因子：
8.8
通讯作者：
Akira, Shizuo
中科院分区：
文献类型：
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作者：
Maruyama, Kenta;Takayama, Yasunori;Akira, Shizuo
白色念珠菌可以通过免疫功能低下宿主的皮肤伤口或骨科手术期间的污染进入骨骼组织。这种念珠菌骨髓炎伴有剧烈疼痛和骨质破坏。已经确定伤害感受器神经支配发生在皮肤和骨骼中，但真菌炎症中伤害感受调节的机制仍不清楚。在这项研究中，我们发现白色念珠菌通过 β-葡聚糖受体 Dectin-1 刺激 Nav1.8 阳性伤害感受器，诱导降钙素基因相关肽 (CGRP)。 CGRP 的这种诱导独立于 Bcl-10 或 Malt-1，但依赖于瞬时受体电位阳离子通道亚家族 V 成员 1 (TRPV1)/瞬时受体电位阳离子通道亚家族 A 成员 1 (TRPA1) 离子通道。在 av1.8 阳性伤害感受器消融或 TRPV1/TRPA1 缺陷后注射 Hindpaw β-葡聚糖显示骨炎症显着增加，并伴有 CGRP 产生受损。引人注目的是，CGRP 分别通过转录阻遏物 Jdp2 直接抑制核因子 kappa B (NF-kappa B) p65 和抑制肌动蛋白聚合来抑制 β-葡聚糖诱导的炎症和破骨细胞多核。这些发现清楚地表明 Dectin-1 介导的感觉分泌通路在解决真菌性骨炎症中的作用。
Candida albicans can enter skeletal tissue through a skin wound in an immunocompromised host or by contamination during orthopedic surgery. Such Candida osteomyelitis is accompanied by severe pain and bone destruction. It is established that nociceptor innervation occurs in skin and bone, but the mechanisms of nociceptive modulation in fungal inflammation remain unclear. In this study, we show that C. albicans stimulates Nav1.8-positive nociceptors via the beta-glucan receptor Dectin-1 to induce calcitonin gene-related peptide (CGRP). This induction of CGRP is independent of Bcl-10 or Malt-1 but dependent on transient receptor potential cation channel subfamily V member 1 (TRPV1)/transient receptor potential cation channel subfamily A member 1 (TRPA1) ion channels. Hindpaw beta-glucan injection after av1.8-positive nociceptor ablation or in TRPV1/TRPA1 deficiency showed dramatically increased osteoinflammation accompanied by impaired CGRP production. Strikingly, CGRP suppressed beta-glucan-induced inflammation and osteoclast multinucleation via direct suppression of nuclear factor-kappa B (NF-kappa B) p65 by the transcriptional repressor Jdp2 and inhibition of actin polymerization, respectively. These findings clearly suggest a role for Dectin-1-mediated sensocrine pathways in the resolution of fungal osteoinflammation.