Peripheral Nerve Resident Macrophages and Schwann Cells Mediate Cancer-Induced Pain

Abstract

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. MΦcolony 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. SignificanceSchwann cell TRPA1 sustains cancer pain through release of M-CSF and oxidative stress, which promote the expansion and the proalgesic actions of intraneural macrophages.

CGRP Signals from Endosomes of Schwann Cells to Elicit Migraine Pain

“…Schwann cells from rat sciatic nerve respond to CGRP by increasing intracellular cAMP levels 25 and CLR/RAMP1 are expressed by Schwann cells that wrap CGRP + ve terminals of rat nociceptors 23,26,27 . Schwann cells mediate mechanical allodynia in mouse models of neuropathic and cancer pain 28,29 . Cutaneous Schwann cells can also directly activate sensory nerves to promote mechanical nociception 30 .…”

β2-and β3-Adrenergic Receptors Contribute to Cancer-Evoked Pain in a Mouse Model of Osteosarcoma via Modulation of Neural Macrophages

“…We previously observed that the development of mechanical allodynia in several neuropathic pain models ( De Logu et al, 2017 ; De Logu et al, 2020a ; De Logu et al, 2020b ; De Logu et al, 2021 ) was associated with the increase in monocytes/macrophages inside the sciatic nerve ipsilateral to the injury. Thus, based on results showing the efficacy of β-AR antagonism to reduce the mechanical allodynia ( Figure 2B ), we then investigated whether the number of macrophages recruited in tibial nerve of osteosarcoma-bearing mice, could be modulated by β-AR antagonists administration.…”

“…It has been known that the increase in macrophages number evokes an increase in oxidative stress at the tissue level, leading to the development of pain ( De Logu et al, 2017 ; De Logu et al, 2020a ; De Logu et al, 2020b ; De Logu et al, 2021 ). Accordingly, in the tibial nerve of K7M2 osteosarcoma-bearing mice, we observed an increase in H 2 O 2 levels compared to sham mice ( Figure 3C ), and the repeated treatment with propranolol and SR59230A, but not with atenolol, significantly reduced the increase in H 2 O 2 levels in tibial nerve ( Figure 3C ).…”

“…First, we showed that the osteosarcoma-bearing mice developed a sustained mechanical allodynia, starting from day 10 after K7M2 osteosarcoma cells inoculation, that was absent in sham mice. Then, based on previous data that showed the pivotal role of peripheral nerve macrophages in the development of pain in mouse models of neuropathic and cancer pain ( De Logu et al, 2017 ; De Logu et al, 2020a ; De Logu et al, 2021 ), we wondered whether also in this cancer model, macrophages in the peripheral (tibial) nerve, which runs ipsilateral to the tumor, played a role in the development and maintenance of mechanical allodynia. Data showed that the number of neural macrophages in the tibial nerve of osteosarcoma-bearing mice were clearly increased compared to sham mice.…”

“…Numerous receptors and their activators have been studied for a better understanding of the cancer pain mechanisms. These comprise the transient receptor potential (TRP) channels, including the vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) subtypes which are involved in bone ( Ghilardi et al, 2005 ), and melanoma ( Antoniazzi et al, 2019 ; De Logu et al, 2021 ) cancer pain models, respectively. The contribution of the acid-sensing ion channels (ASICs) has been reported in an osteolysis-induced bone cancer pain ( Nagae et al, 2007 ) and the protease-activator receptor 2 (PAR2) in peripheral neurons is the target of serine proteases and tryptase released from cancer cells to promote the prolonged mechanical allodynia in mouse cancer nociceptive models ( Lam and Schmidt, 2010 ).…”