Thromboxane-Induced α-CGRP Release from Peripheral Neurons Is an Essential Positive Feedback Loop in Capsaicin-Induced Neurogenic Inflammation

Tarighi, Neda; Menger, Dominic; Pierre, Sandra; Kornstädt, Lisa; Thomas, Dominique; Ferreiròs, Nerea; Nüsing, Rolf M.; Geißlinger, Gerd; Scholich, Klaus

doi:10.1016/j.jid.2018.10.011

Cited by 11 publications

(7 citation statements)

References 57 publications

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“…The levels of LTB 4 were also reduced in the Kras G12D /BLT2-KO mice (Fig. 4h ), consistent with the feedback regulatory mechanism between eicosanoid receptors and their ligands 40 , 41 . IL-6 expression was also reduced in the Kras G12D /BLT2-KO mice compared with the Kras G12D mice (Fig.…”

Section: Resultssupporting

confidence: 75%

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Leukotriene B4 receptor-2 contributes to KRAS-driven lung tumor formation by promoting interleukin-6-mediated inflammation

Jang

Park

et al. 2021

Exp Mol Med

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Although lung cancer is the leading cause of cancer-related deaths worldwide and KRAS is the most frequently mutated oncogene in lung cancer cases, the mechanism by which KRAS mutation drives lung cancer has not been fully elucidated. Here, we report that the expression levels of leukotriene B4 receptor-2 (BLT2) and its ligand-producing enzymes (5-LOX, 12-LOX) were highly increased by mutant KRAS and that BLT2 or 5-/12-LOX blockade attenuated KRAS-driven lung cell proliferation and production of interleukin-6 (IL-6), a principal proinflammatory mediator of lung cancer development. Next, we explored the roles of BLT2 and 5-/12-LOX in transgenic mice with lung-specific expression of mutant KRAS (KrasG12D) and observed that BLT2 or 5-/12-LOX inhibition decreased IL-6 production and tumor formation. To further determine whether BLT2 is involved in KRAS-driven lung tumor formation, we established a KrasG12D/BLT2-KO double-mutant mouse model. In the double-mutant mice, we observed significantly suppressed IL-6 production and lung tumor formation. Additionally, we observed high BLT2 expression in tissue samples from patients with KrasG12D-expressing lung adenocarcinoma, supporting the contributory role of BLT2 in KRAS-driven human lung cancer. Collectively, our results suggest that BLT2 is a potential contributor to KRAS-driven lung cancer and identify an attractive therapeutic target for KRAS-driven lung cancer.

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Section: Resultssupporting

confidence: 75%

“…4h and Supplementary Fig. 3 ), and this feedback regulation is frequently observed in eicosanoid receptors 40 , 41 . In this tumor-friendly environment, BLT2-mediated autocrine positive feedback loops could lead to more aggressive amplification of tumor progression 52 – 54 .…”

Section: Discussionmentioning

confidence: 69%

Leukotriene B4 receptor-2 contributes to KRAS-driven lung tumor formation by promoting interleukin-6-mediated inflammation

Jang

Park

et al. 2021

Exp Mol Med

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“…Liquid chromatography-tandem mass spectrometry of prostanoids and linoleic acid metabolites. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of prostanoids in sciatic nerve, DRG, and dorsal spinal cord tissue samples was in general performed as described previously (Tarighi et al, 2019). Briefly, tissue was dissected, weighted, and immediately transferred into liquid nitrogen.…”

Section: Methodsmentioning

confidence: 99%

Lysophospholipids Contribute to Oxaliplatin-Induced Acute Peripheral Pain

et al. 2020

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Oxaliplatin, a platinum-based chemotherapeutic drug, which is used as first-line treatment for some types of colorectal carcinoma, causes peripheral neuropathic pain in patients. In addition, an acute peripheral pain syndrome develop in almost 90% of patients immediately after oxaliplatin treatment, which is poorly understood mechanistically but correlates with incidence and severity of the later-occurring neuropathy. Here we investigated the effects of acute oxaliplatin treatment in a murine model, showing that male and female mice develop mechanical hypersensitivity 24 h after oxaliplatin treatment. Interestingly, we found that the levels of several lipids were significantly altered in nervous tissue during oxaliplatin-induced acute pain. Specifically, the linoleic acid metabolite 9,10-EpOME (epoxide of linoleic acid) as well as the lysophospholipids lysophosphatidylcholine (LPC) 18:1 and LPC 16:0 were significantly increased 24 h after oxaliplatin treatment in sciatic nerve, DRGs, or spinal cord tissue as revealed by untargeted and targeted lipidomics. In contrast, inflammatory markers including cytokines and chemokines, ROS markers, and growth factors are unchanged in the respective nervous system tissues. Importantly, LPC 18:1 and LPC 16:0 can induce Ca 21 transients in primary sensory neurons, and we identify LPC 18:1 as a previously unknown endogenous activator of the ligand-gated calcium channels transient receptor potential V1 and M8 (transient receptor potential vanilloid 1 and transient receptor potential melastatin 8) in primary sensory neurons using both pharmacological inhibition and genetic knockout. Additionally, a peripheral LPC 18:1 injection was sufficient to induce mechanical hypersensitivity in naive mice. Hence, targeting signaling lipid pathways may ameliorate oxaliplatin-induced acute peripheral pain and the subsequent long-lasting neuropathy.

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“…Mast cell activation can also induce de novo synthesis and release of lipid mediators (e.g. prostaglandin (PG) E2 and thromboxane), cytokines and chemokines (1,2). The precise response and signaling pathway activated in a mast cell depends on the stimulus activating the cell, which can be recognized and discriminated by an extensive repertoire of receptors.…”

Section: Introductionmentioning

confidence: 99%

Bacterial and Fungal Toll-Like Receptor Activation Elicits Type I IFN Responses in Mast Cells

et al. 2021

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Next to their role in IgE-mediated allergic diseases and in promoting inflammation, mast cells also have antiinflammatory functions. They release pro- as well as antiinflammatory mediators, depending on the biological setting. Here we aimed to better understand the role of mast cells during the resolution phase of a local inflammation induced with the Toll-like receptor (TLR)-2 agonist zymosan. Multiple sequential immunohistology combined with a statistical neighborhood analysis showed that mast cells are located in a predominantly antiinflammatory microenvironment during resolution of inflammation and that mast cell-deficiency causes decreased efferocytosis in the resolution phase. Accordingly, FACS analysis showed decreased phagocytosis of zymosan and neutrophils by macrophages in mast cell-deficient mice. mRNA sequencing using zymosan-induced bone marrow-derived mast cells (BMMC) revealed a strong type I interferon (IFN) response, which is known to enhance phagocytosis by macrophages. Both, zymosan and lipopolysaccharides (LPS) induced IFN-β synthesis in BMMCs in similar amounts as in bone marrow derived macrophages. IFN-β was expressed by mast cells in paws from naïve mice and during zymosan-induced inflammation. As described for macrophages the release of type I IFNs from mast cells depended on TLR internalization and endosome acidification. In conclusion, mast cells are able to produce several mediators including IFN-β, which are alone or in combination with each other able to regulate the phagocytotic activity of macrophages during resolution of inflammation.

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Thromboxane-Induced α-CGRP Release from Peripheral Neurons Is an Essential Positive Feedback Loop in Capsaicin-Induced Neurogenic Inflammation

Cited by 11 publications

References 57 publications

Leukotriene B4 receptor-2 contributes to KRAS-driven lung tumor formation by promoting interleukin-6-mediated inflammation

Leukotriene B4 receptor-2 contributes to KRAS-driven lung tumor formation by promoting interleukin-6-mediated inflammation

Lysophospholipids Contribute to Oxaliplatin-Induced Acute Peripheral Pain

Bacterial and Fungal Toll-Like Receptor Activation Elicits Type I IFN Responses in Mast Cells

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