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Comparisons of cigarette smoke- (CS-) induced oxidative stress and lung inflammatory score in wild-type and trpa1−/− mice. Mice were chronically exposed to air or CS for 4 weeks. (a) Levels of ROS in the bronchoalveolar lavage fluid (BALF) were sampled immediately after the last air or CS exposure across the four study groups. Levels of ROS were measured by DCFH-DA fluorescent probe assay. (b) Expression of 4-HNE modified protein, a biomarker of oxidative stress, in lung tissues was analyzed by Western blotting. (c) Representative images of H&E stained lung sections obtained from air-exposure or CS-exposure wild-type and trpa1−/− mice. (d) Lung inflammatory scores were calculated according to the sum of the levels of cell infiltration and damage levels assessed from the lung sections. Data in each group are mean ± SEM from nine mice. p∗<0.05 versus the air-exposure group in both genotypes; #p<0.05 versus the CS-exposure wild-type group.
Source publication
The mechanism underlying the inflammatory role of TRPA1 in lung epithelial cells (LECs) remains unclear. Here, we show that cigarette smoke extract (CSE) sequentially induced several events in LECs. The Ca
2+
influx was prevented by decreasing extracellular reactive oxygen species (ROS) with the scavenger N-acetyl-cysteine, removing extracellular C...
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Objective
To explore the effect of cigarette smoke (CS) on the development of squamous metaplasia in human airway epithelial cells and the role of MAPK- and FoxA2-signaling pathways in the process.
Materials and methods
In an in vitro study, we treated the bronchial epithelial cell line BEAS2B with CS extract, followed by treatment with the ERK in...
Citations
... Our results agree with previous findings, which show that TRPA1 activation also leads to the production of inflammatory cytokines (Yap et al. 2020). The calcium influx promoted by TRPA1 after oxidant compounds gating could maintain the continuous activation of pro-oxidizing enzymes (as NADPH oxidase), which in turn provoke mitogen-activated protein kinases (MAPKs) or/and NF-κB signaling (Antoniazzi et al. 2018;Lee et al. 2016;Lin et al. 2015). The TRPA1 antagonism may reduce the production of oxidant compounds impairing the further activation of NF-kB and/or MAPK, which could cause the increased expression of inflammatory genes and the TRPA1 channels in the injured muscle (Antoniazzi et al. 2018;Hatano et al. 2012;Kondo et al. 2013;Lin et al. 2015;Volpi et al. 2011). ...
... The calcium influx promoted by TRPA1 after oxidant compounds gating could maintain the continuous activation of pro-oxidizing enzymes (as NADPH oxidase), which in turn provoke mitogen-activated protein kinases (MAPKs) or/and NF-κB signaling (Antoniazzi et al. 2018;Lee et al. 2016;Lin et al. 2015). The TRPA1 antagonism may reduce the production of oxidant compounds impairing the further activation of NF-kB and/or MAPK, which could cause the increased expression of inflammatory genes and the TRPA1 channels in the injured muscle (Antoniazzi et al. 2018;Hatano et al. 2012;Kondo et al. 2013;Lin et al. 2015;Volpi et al. 2011). Then, interestingly, our muscle injury model caused increased mRNA levels for Trpa1 in the gastrocnemius muscle and dorsal root ganglia. ...
Musculoskeletal pain is a widely experienced public healthcare issue, especially after traumatic muscle injury. Besides, it is a common cause of disability, but this pain remains poorly managed. However, the pathophysiology of traumatic muscle injury-associated pain and inflammation has not been fully elucidated. In this regard, the transient receptor potential ankyrin 1 (TRPA1) has been studied in inflammatory and painful conditions. Thus, this study aimed to evaluate the antinociceptive and anti-inflammatory effect of the topical application of a TRPA1 antagonist in a model of traumatic muscle injury in rats. The mechanical trauma model was developed by a single blunt trauma impact on the right gastrocnemius muscle of Wistar male rats (250–350 g). The animals were divided into four groups (Sham/Vehicle; Sham/HC-030031 0.05%; Injury/Vehicle, and Injury/HC-030031 0.05%) and topically treated with a Lanette® N cream base containing a TRPA1 antagonist (HC-030031, 0.05%; 200 mg/muscle) or vehicle (Lanette® N cream base; 200 mg/muscle), which was applied at 2, 6, 12, 24, and 46 h after muscle injury. Furthermore, we evaluated the contribution of the TRPA1 channel on nociceptive, inflammatory, and oxidative parameters. The topical application of TRPA1 antagonist reduced biomarkers of muscle injury (lactate/glucose ratio), spontaneous nociception (rat grimace scale), inflammatory (inflammatory cell infiltration, cytokine levels, myeloperoxidase, and N-acetyl-β-d-glucosaminidase activities) and oxidative (nitrite levels and dichlorofluorescein fluorescence) parameters, and mRNA Trpa1 levels in the muscle tissue. Thus, these results demonstrate that TRPA1 may be a promising anti-inflammatory and antinociceptive target in treating muscle pain after traumatic muscle injury.
... TRPA1 is known to be induced and activated by cigarette smoke extract [24,25]. Acrolein is also known as a compound that activates TRPA1; however, the involvement of TRPA1 in acrolein toxicity has not been clarified in detail. ...
... It has been reported that cigarette smoke extract containing acrolein induces TRPA1 expression [24,26]. Therefore, we analyzed whether acrolein induces TRPA1 expression in A549 cells using western blot analysis and qRT-PCR. ...
... Previous studies have reported that TRPA1 is induced by cigarette smoke and contributes to the inflammatory response [24]. Cigarette smoking is a risk factor for lung cancer, contributing to lung cancer progression and metastasis. ...
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective ion channel implicated in thermosensation and inflammatory pain. It has been reported that expression of the TRPA1 channel is induced by cigarette smoke extract. Acrolein found in cigarette smoke is highly toxic and known as an agonist of the TRPA1 channel. However, the role of TRPA1 in the cytotoxicity of acrolein remains unclear. Here, we investigated whether the TRPA1 channel is involved in the cytotoxicity of acrolein in human lung cancer A549 cells. The IC50 of acrolein in A549 cells was 25 μM, and acrolein toxicity increased in a concentration- and time-dependent manner. When the effect of acrolein on TRPA1 expression was examined, the expression of TRPA1 in A549 cells was increased by treatment with 50 μM acrolein for 24 h or 500 μM acrolein for 30 min. AP-1, a transcription factor, was activated in the cells treated with 50 μM acrolein for 24 h, while induction of NF-κB and HIF-1α was observed in the cells treated with 500 μM acrolein for 30 min. These results suggest that acrolein induces TRPA1 expression by activating these transcription factors. Overexpression of TRPA1 in A549 cells increased acrolein sensitivity and the level of protein-conjugated acrolein (PC-Acro), while knockdown of TRPA1 in A549 cells or treatment with a TRPA1 antagonist caused tolerance to acrolein. These findings suggest that acrolein induces the TRPA1 channel and that an increase in TRPA1 expression promotes the cytotoxicity of acrolein.
... Endogenous TRPA1 activators are produced in inflammatory reactions, including reactive oxygen and nitrogen species [5][6][7][8]. More recently, TRPA1 has been found to be expressed also in non-neuronal cells, including chondrocytes [9], keratinocytes [10][11][12] and lung epithelial cells [13][14][15], and to regulate the expression of inflammatory factors such as interleukin 8 (IL-8), interleukin 6 (IL-6) and prostaglandin E 2 [9,[13][14][15][16][17][18][19][20][21][22][23]. ...
... TRPA1 seems to be important in the pathogenesis of inflammatory lung diseases. TRPA1 is activated by cigarette smoke to cause inflammation and hyperreactivity [4,17,19], epithelial cell damage [17,19] and emphysema [24]. In the ovalbumin model of allergic asthma, TRPA1 has been reported to promote the release of inflammatory factors [25][26][27][28][29], mediate peripheral blood eosinophilia [27,29], increase leukocyte influx to the lungs [22,25,[27][28][29] and to increase airway hyperreactivity [25,26,28,29]. ...
... TRPA1 seems to be important in the pathogenesis of inflammatory lung diseases. TRPA1 is activated by cigarette smoke to cause inflammation and hyperreactivity [4,17,19], epithelial cell damage [17,19] and emphysema [24]. In the ovalbumin model of allergic asthma, TRPA1 has been reported to promote the release of inflammatory factors [25][26][27][28][29], mediate peripheral blood eosinophilia [27,29], increase leukocyte influx to the lungs [22,25,[27][28][29] and to increase airway hyperreactivity [25,26,28,29]. ...
Background
Transient Receptor Potential Ankyrin 1 (TRPA1) is a cation channel that mediates pain, itch, cough, and neurogenic inflammation in response to pungent compounds such as acrolein in cigarette smoke. TRPA1 is also activated by endogenous factors and promotes inflammation in asthma models. We have recently shown that TRPA1 is upregulated by inflammatory cytokines in A549 human lung epithelial cells. Here, we explored the effects of Th1 and Th2-type inflammation on TRPA1.
Methods and results
TRPA1 expression and function was studied in A549 human lung epithelial cells. To induce inflammation, the cells were exposed to a combination of cytokines TNF-α and IL-1β; and to model Th1 or Th2-type responses, IFN-γ or IL-4/IL-13 was added, respectively. TRPA1 expression (measured by RT-PCR and Western blot) and function (assessed by Fluo-3AM intracellular calcium measurement) was enhanced under the influence of TNF-α + IL-1β. IFN-γ further enhanced TRPA1 expression and function, whereas IL-4 and IL-13 suppressed them. The effects of IFN-γ and IL-4 on TRPA1 expression were reversed by the Janus kinase (JAK) inhibitors baricitinib and tofacitinib, and those of IL-4 also by the STAT6 inhibitor AS1517499. The glucocorticoid dexamethasone downregulated TRPA1 expression, whereas the PDE4 inhibitor rolipram had no effect. Under all conditions, TRPA1 blockade was found to reduce the production of LCN2 and CXCL6.
Conclusions
TRPA1 expression and function in lung epithelial cells was upregulated under inflammatory conditions. IFN-γ further increased TRPA1 expression while IL-4 and IL-13 suppressed that in a JAK-STAT6 dependent manner which is novel. TRPA1 also modulated the expression of genes relevant to innate immunity and lung disease. We propose that the paradigm of Th1 and Th2 inflammation is a major determinant of TRPA1 expression and function, which should be considered when targeting TRPA1 for pharmacotherapy in inflammatory (lung) disease.
... TRPA1 coordinates a series of cellular processes such as cytokine production through indirect regulation of the intracellular pathways . The inflammatory factors mediating TRPA1 activation and proinflammatory response include interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) (Bautista et al., 2013;Lin et al., 2015;Feng et al., 2017;Kanda et al., 2018). ...
Recently, increasing numbers of studies have demonstrated that transient receptor potential ankyrin 1 (TRPA1) can be used as a potential target for the treatment of inflammatory diseases. TRPA1 is expressed in both neuronal and non-neuronal cells and is involved in diverse physiological activities, such as stabilizing of cell membrane potential, maintaining cellular humoral balance, and regulating intercellular signal transduction. TRPA1 is a multi-modal cell membrane receptor that can sense different stimuli, and generate action potential signals after activation via osmotic pressure, temperature, and inflammatory factors. In this study, we introduced the latest research progress on TRPA1 in inflammatory diseases from three different aspects. First, the inflammatory factors released after inflammation interacts with TRPA1 to promote inflammatory response; second, TRPA1 regulates the function of immune cells such as macrophages and T cells, In addition, it has anti-inflammatory and antioxidant effects in some inflammatory diseases. Third, we have summarized the application of antagonists and agonists targeting TRPA1 in the treatment of some inflammatory diseases.
... Importantly, it can be further noted that the inhibitory effects of Cur on Caco-2 cell proliferation were related to the activation of the TRPA1 channel. Results of CCK-8 assay (Fig. 1E) and EdU assay ( Fig. 1F and 1G) showed that HC-030031 (HC), a potent and selective TRPA1 inhibitor, efficiently blocked the anti-proliferative effects of Cur on Caco-2 cells at a concentration of 9 µM (the same concentration used in the experiment about the inflammatory role of TRPA1 in lung epithelial cells [38]). Moreover, Cur treatment significantly downregulated protein expression of the cell cycle regulator, Cyclin D1, and this inhibitory effect was reversed by HC (Fig. 1H). ...
Background
Curcumin (Cur) is a bioactive dietary polyphenol of turmeric with various biological activities against several cancers. Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Intestinal cholesterol homeostasis is associated with CRC. Chemotherapy for CRC is related to varied adverse effects. Therefore, natural products with anti-cancer properties represent a potential strategy for primary prevention of CRC.
Methods
The present study used Cur as a therapeutic approach against CRC using the Caco-2 cell line. The cells were treated with different concentrations of Cur for different duration of time and then the proliferation ability of cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2′-deoxyuridine assays. Oil red O staining and cholesterol assay kit were used to evaluate cellular lipid content and cholesterol outward transportation. Finally, the protein expressions of cholesterol transport-related protein and signal transduction molecules were assessed using Western blot assay.
Results
Cur inhibited cell proliferation in Caco-2 cells in a dose- and time-dependent manner by activating the transient receptor potential cation channel subfamily A member 1 (TRPA1) channel. Activation of the TRPA1 channel led to increased intracellular calcium, peroxisome proliferator-activated receptor gamma (PPARγ) upregulation, and the subsequent downregulation of the specificity protein-1 (SP-1)/sterol regulatory element-binding protein-2 (SREBP-2)/Niemann-Pick C1-like 1 (NPC1L1) signaling pathway-related proteins, and finally reduced cholesterol absorption in Caco-2 cells.
Conclusions
Cur inhibits cell proliferation and reduces cholesterol absorption in Caco-2 cells through the Ca ²⁺ /PPARγ/SP-1/SREBP-2/NPC1L1 signaling by activating the TRPA1 channel, suggesting that Cur can be used as a dietary supplement for the primary prevention of CRC.
Graphical Abstract
In Caco-2 cells, Cur first stimulates calcium influx by activating the TRPA1 channel, further upregulates PPARγ and downregulates SP-1/SREBP-2/NPC1L1 signaling pathway, and finally inhibits the absorption of cholesterol. TRPA1, transient receptor potential cation channel subfamily A member 1; NPC1L1, Niemann-Pick C1-like 1; PPARγ, peroxisome proliferator-activated receptor gamma; SP-1, specificity protein-1; SREBP-2, sterol regulatory element-binding protein-2; Cur, curcumin.
... Cells were preloaded with the cytosol ROS indicator DCFH-DA (10 μM, Sigma) or the mitochondrial ROS (mtROS) indicator MitoSOX Red (2.5 μM, Molecular Probes, USA) for 15 min and then treated with AuNPs and LPS for 4 h. A liquid ROS detection kit (BestBio, China) was used to supplement ROS in the cell culture supernatant [61]. Cytosolic ROS and mtROS levels were measured using an ACEA NovoCyte flow cytometer system (San Diego, CA, USA). ...
Background
Gold nanoparticles (AuNPs) are increasingly utilized in industrial and biomedical fields, thereby demanding a more comprehensive knowledge about their safety. Current toxicological studies mainly focus on the unfavorable biological impact governed by the physicochemical properties of AuNPs, yet the consequences of their interplay with other bioactive compounds in biological systems are poorly understood.
Results
In this study, AuNPs with a size of 10 nm, the most favorable size for interaction with host cells, were given alone or in combination with bacterial lipopolysaccharide (LPS) in mice or cultured hepatic cells. The results demonstrated that co exposure to AuNPs and LPS exacerbated fatal acute liver injury (ALI) in mice, although AuNPs are apparently non-toxic when administered alone. AuNPs do not enhance systemic or hepatic inflammation but synergize with LPS to upregulate hepatic apoptosis by augmenting macrophage-hepatocyte crosstalk. Mechanistically, AuNPs and LPS coordinate to upregulate NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) generation and activate the intrinsic apoptotic pathway in hepatic macrophages. Extracellular ROS generation from macrophages is then augmented, thereby inducing calcium-dependent ROS generation and promoting apoptosis in hepatocytes. Furthermore, AuNPs and LPS upregulate scavenger receptor A expression in macrophages and thus increase AuNP uptake to mediate further apoptosis induction.
Conclusions
This study reveals a profound impact of AuNPs in aggravating the hepatotoxic effect of LPS by amplifying ROS-dependent crosstalk in hepatic macrophages and hepatocytes.
Graphical Abstract
... The link between ROS and inflammation in the lung has been explored (Madreiter-Sokolowski et al., 2020). Lin et al. (2015) found that CSE increased the levels of ROS in lung epithelial cells, which activated transient receptor potential ankyrin 1, increased Ca 2+ influx, activated the MAPKs/NF-κB signaling pathway, and ultimately induced the expression of IL-8. Intracellular Ca 2+ response can be completed inhibited by NAC (Lin et al., 2015). ...
... Lin et al. (2015) found that CSE increased the levels of ROS in lung epithelial cells, which activated transient receptor potential ankyrin 1, increased Ca 2+ influx, activated the MAPKs/NF-κB signaling pathway, and ultimately induced the expression of IL-8. Intracellular Ca 2+ response can be completed inhibited by NAC (Lin et al., 2015). Previous studies have identified STIM1 as an important oxidative stress sensor (Hawkins et al., 2010) and an ER transmembrane protein (Soboloff et al., 2012), which senses the reduction of Ca 2+ in the ER and promote inflammatory responses (Liou et al., 2005;Chen et al., 2013). ...
Chronic obstructive pulmonary disease (COPD), primarily attributed to cigarette smoke (CS), is characterized by multiple pathophysiological changes, including oxidative stress and inflammation. Stromal interaction molecule 1 (STIM1) is a Ca²⁺ sensor that regulates Ca²⁺ entry in different types of cells. The present study aimed to explore the relationship between CS-induced oxidative stress and inflammation, as well as the functional role of STIM1 thereinto. Our results showed that the reactive oxygen species (ROS)/STIM1/Ca²⁺ axis played a critical role in CS-induced secretion of interleukin (IL)-8 in human alveolar macrophages. Specifically, smokers with COPD (SC) showed higher levels of ROS in the lung tissues compared with healthy non-smokers (HN). STIM1 was upregulated in the lung tissues of COPD patients. The expression of STIM1 was positively associated with ROS levels and negatively correlated with pulmonary function. The expression of STIM1 was also increased in the bronchoalveolar lavage fluid (BALF) macrophages of COPD patients and PMA-differentiated THP-1 macrophages stimulated by cigarette smoke extract (CSE). Additionally, CSE-induced upregulation of STIM1 in PMA-differentiated THP-1 macrophages was inhibited by pretreatment with N-acetylcysteine (NAC), a ROS scavenger. Transfection with small interfering RNA (siRNA) targeting STIM1 and pretreatment with NAC alleviated CSE-induced increase in intracellular Ca²⁺ levels and IL-8 expression. Furthermore, pretreatment with SKF-96365 and 2-APB, the inhibitors of Ca²⁺ influx, suppressed CSE-induced secretion of IL-8. In conclusion, our study demonstrates that CSE-induced ROS production may increase the expression of STIM1 in macrophages, which further promotes the release of IL-8 by regulating Ca²⁺ entry. These data suggest that STIM1 may play a crucial role in CSE-induced ROS production and inflammation, and participate in the pathogenesis of COPD.
... 2+ influx is mediated by the TRPA1 channel. After establishing SOCC and LTCC as unlikely targets activated by CS/CSE, a possible alternative candidate was TRPA1, a Ca 2+ -permeable cation channel that has been shown to mediate CSE-induced Ca 2+ increases in other cell types 23,[26][27][28] . We used the inhibitor HC-030031 to study the involvement of TRPA1. ...
... TRPA1 is known to be activated by several components found in CS, namely acrolein, crotonaldehyde, extracellular ROS, and nicotine, in neuronal and lung epithelial cells, and is required to mediate neurogenic www.nature.com/scientificreports/ inflammation and pain following CS exposure 23,28,[31][32][33] . These constituents, individually or together, are likely responsible for the rapid CS/CSE-induced activation of TRPA1 in hASMC; further exploration studying the role of each individual constituent on hASMC Ca 2+ influx, as well as modulation of physiological Ca 2+ responses, is therefore warranted. ...
Tobacco smoking is the largest risk factor for developing chronic obstructive pulmonary disease (COPD), and is associated with hyperresponsiveness of airway smooth muscle (ASM). Chronic exposure to cigarette smoke (CS) leads to airway inflammation and remodelling. However, the direct effect of gaseous CS or CS extract (CSE) on human airway smooth muscle cell (hASMC) function remains poorly understood. This study investigated the acute effect of CS/CSE on calcium homeostasis, a key regulator of ASM physiology and pathophysiology. Primary hASMC were isolated from non-smoking donor lungs, and subjected to Ca²⁺ imaging studies. We found that both CS, and CSE, rapidly elevated cytosolic Ca²⁺ in hASMC through stimulation of plasmalemmal Ca²⁺ influx, but excluded store-operated and L-type Ca²⁺ channels as mediators of this effect. Using a specific pharmacological inhibitor, or shRNA-driven knockdown, we established that both CS and CSE stimulated Ca²⁺ influx in hASMC through the neurogenic pain receptor channel, transient receptor potential ankyrin 1 (TRPA1). CS/CSE-dependent, TRPA1-mediated Ca²⁺ influx led to myosin light-chain phosphorylation, a key process regulating ASM contractility. We conclude that TRPA1 is likely an important link between CS/CSE exposure and airway hyperresponsiveness, and speculate that acute CS/CSE-induced Ca²⁺ influx could lead to exacerbated ASM contraction and potentially initiate further chronic pathological effects of tobacco smoke.
... The stimulation of the lung epithelial cells by cigarette smoke, a major oxidant, increases the TRPA1 mediated production of IL-8. In mice, epithelial TRPA mediates lung inflammation due to cigarette smoke [99,100]. TRPA1, expressed in cardiac myocytes, plays a role in the regulation of myocardial reperfusion injury. ...
TRPA1, a nonselective cation channel, is expressed in sensory afferent that innervates peripheral targets. Neuronal TRPA1 can promote tissue repair, remove harmful stimuli and induce protective responses via the release of neuropeptides after the activation of the channel by chemical, exogenous, or endogenous irritants in the injured tissue. However, chronic inflammation after repeated noxious stimuli may result in the development of several diseases. In addition to sensory neurons, TRPA1, activated by inflammatory agents from some non-neuronal cells in the injured area or disease, might promote or protect disease progression. Therefore, TRPA1 works as a molecular sentinel of tissue damage or as an inflammation gatekeeper. Most kidney damage cases are associated with inflammation. In this review, we summarised the role of TRPA1 in neurogenic or non-neurogenic inflammation and in kidney disease, especially the non-neuronal TRPA1. In in vivo animal studies, TRPA1 prevented sepsis-induced or Ang-II-induced and ischemia-reperfusion renal injury by maintaining mitochondrial haemostasis or via the downregulation of macrophage-mediated inflammation, respectively. Renal tubular epithelial TRPA1 acts as an oxidative stress sensor to mediate hypoxia–reoxygenation injury in vitro and ischaemia–reperfusion-induced kidney injury in vivo through MAPKs/NF-kB signalling. Acute kidney injury (AKI) patients with high renal tubular TRPA1 expression had low complete renal function recovery. In renal disease, TPRA1 plays different roles in different cell types accordingly. These findings depict the important role of TRPA1 and warrant further investigation.
... We then explored the mechanism of M-CSF release from Schwann cells. TRPA1 stimulation has been reported to promote oxidative stress (6,30) and oxidants may release members of the CSF family (31). Exposure of cultured human Schwann cells to the nonreactive (PF-4840154) or reactive (H 2 O 2 ) agonists increased M-CSF levels in the cell supernatant, responses that were attenuated by the TRPA1 antagonist, A967079, and PF-4840154-evoked release of M-CSF was reduced by the antioxidant, phenyl-N-tert-butylnitrone (PBN; Fig. 5C). ...
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.
