Nociceptors Boost the Resolution of Fungal Osteoinflammation via the TRP Channel-CGRP-Jdp2 Axis
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
Affiliations
Kenta Maruyama
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Yasunori Takayama
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8787, Japan
Takeshi Kondo
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Ken-ichi Ishibashi
Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Bikash Ranjan Sahoo
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Hisashi Kanemaru
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Yutaro Kumagai
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Mikaël M. Martino
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Hiroki Tanaka
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Naohito Ohno
Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Yoichiro Iwakura
Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan
Naoki Takemura
Department of Mucosal Immunology, School of Medicine, Chiba University, Chiba 260-8670, Japan
Makoto Tominaga
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8787, Japan
Shizuo Akira
Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
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.
