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

Abstract

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 19 Issue 13 Pg. 2730-2742 (06 27 2017) ISSN: 2211-1247 [Electronic] United States
• PMID: 28658621 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Jundp2 protein, mouse
• Repressor Proteins
• TRPV Cation Channels
• TRPV1 protein, mouse
• Calcitonin Gene-Related Peptide

Topics

• Animals
• Calcitonin Gene-Related Peptide (metabolism)
• Candida albicans (immunology)
• Candidiasis (immunology, metabolism, pathology)
• Female
• Humans
• Inflammation (immunology, microbiology)
• Mice
• Nociceptors (immunology)
• Repressor Proteins (immunology, metabolism)
• TRPV Cation Channels (immunology, metabolism)