Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel-CGRP-Jdp2 Axis

Publication date: 27 June 2017
Source:Cell Reports, Volume 19, Issue 13
Author(s): Kenta Maruyama, Yasunori Takayama, Takeshi Kondo, Ken-ichi Ishibashi, Bikash Ranjan Sahoo, Hisashi Kanemaru, Yutaro Kumagai, Mikaël M. Martino, Hiroki Tanaka, Naohito Ohno, Yoichiro Iwakura, Naoki Takemura, Makoto Tominaga, Shizuo Akira
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 β-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 β-glucan injection after Nav1.8-positive nociceptor ablation or in TRPV1/TRPA1 deficiency showed dramatically increased osteoinflammation accompanied by impaired CGRP production. Strikingly, CGRP suppressed β-glucan-induced inflammation and osteoclast multinucleation via direct suppression of nuclear factor-κB (NF-κB) 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.

Graphical abstract

Teaser

Maruyama et al. find that Nav1.8-positive nociceptors function during in fungal inflammation.


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