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

• Published in: Cell reports (Cambridge) 2017-06, Vol.19 (13), p.2730-2742
• Main Authors: Maruyama, Kenta, Takayama, Yasunori, Kondo, Takeshi, Ishibashi, Ken-ichi, Sahoo, Bikash Ranjan, Kanemaru, Hisashi, Kumagai, Yutaro, Martino, Mikaël M., Tanaka, Hiroki, Ohno, Naohito, Iwakura, Yoichiro, Takemura, Naoki, Tominaga, Makoto, Akira, Shizuo
• Format: Article
• Language: English
• Subjects: Animals; Calcitonin Gene-Related Peptide - metabolism; Candida albicans; Candida albicans - immunology; Candidiasis - immunology; Candidiasis - metabolism; Candidiasis - pathology; Female; Humans; Inflammation - immunology; Inflammation - microbiology; Jdp2; Mice; NF-κB; Nociceptors - immunology; osteoclast; Repressor Proteins - immunology; Repressor Proteins - metabolism; TRPA1; TRPV Cation Channels - immunology; TRPV Cation Channels - metabolism; TRPV1; β-glucan
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.06.002

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. [Display omitted] •Fungi activate neurons via the Dectin-1-TRP channel axis, leading to CGRP production•Nav1.8-positive neurons inhibit osteoporosis and osteomyelitis in response to β-glucan•TRPV1/TRPA1 deficiency exhibits severe osteoinflammation in response to β-glucan•Nociceptor-derived CGRP inhibits β-glucan-induced NF-κB activation via Jdp2 Maruyama et al. find that Nav1.8-positive nociceptors function during in fungal inflammation.