TY - JOUR
T1 - Peripheral Nerve Resident Macrophages and Schwann Cells Mediate Cancer-Induced Pain
AU - de Logu, Francesco
AU - Marini, Matilde
AU - Landini, Lorenzo
AU - de Araujo, Daniel Souza Monteiro
AU - Bartalucci, Niccolo
AU - Trevisan, Gabriela
AU - Bruno, Gennaro
AU - Marangoni, Martina
AU - Schmidt, Brian L.
AU - Bunnett, Nigel W.
AU - Geppetti, Pierangelo
AU - Nassini, Romina
N1 - Funding Information:
We thank D. Preti (University of Ferrara, Ferrara, Italy) for providing A967079. This work was supported by European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 835286; to P. Geppetti), Associazione Italiana per la Ricerca sul Cancro (AIRC, IG2016-ID19247 and IG2020-ID24503) and Fondazione Cassa di Risparmio di Firenze, Italy (to R. Nassini), NIH (NS102722, DE026806, DK118971, DE029951 to N.W. Bunnett and B.L. Schmidt), and Department of Defense (W81XWH1810431 to N.W. Bunnett and B.L. Schmidt).
Funding Information:
N.W. Bunnett reports grants from NIH and Department of Defense during the conduct of the study, nonfinancial support from Endosome Therapeutics Inc. outside the submitted work, and is a founding scientist of Endosome Therapeutics Inc. P. Geppetti reports grants and personal fees from Eli-Lilly, TEVA, Novartis, Allergan/ AbbVie, and grants from Lundbeck outside the submitted work and is a founding scientist of FloNext Srl. R. Nassini is a founding scientist of FloNext Srl. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6
Y1 - 2021/6
N2 - Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of
Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. SIGNIFICANCE: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3387/F1.large.jpg.
AB - Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of
Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress, and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain. SIGNIFICANCE: Schwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3387/F1.large.jpg.
KW - Animals
KW - Cancer Pain/etiology
KW - Female
KW - Hyperalgesia/etiology
KW - Lung Neoplasms/complications
KW - Macrophages/immunology
KW - Male
KW - Melanoma, Experimental/complications
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Peripheral Nerves/immunology
KW - Schwann Cells/immunology
KW - TRPA1 Cation Channel/physiology
UR - http://www.scopus.com/inward/record.url?scp=85107984618&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107984618&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-3326
DO - 10.1158/0008-5472.CAN-20-3326
M3 - Article
C2 - 33771895
AN - SCOPUS:85107984618
VL - 81
SP - 3387
EP - 3401
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 12
ER -