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Mast cell CRFR1 contributes to pancreatic cancer pain via MAPK/SPHK1 signaling

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer often accompanied by persistent abdominal pain and stress, significantly compromising patients’ quality of life. Previous studies have identified mast cells as crucial contributors to pancreatic cancer related pain. This study aimed to investigate the role of the mast cell receptor CRFR1 and delineate its underlying mechanisms in mediating pancreatic pain. In the current study, we demonstrated that painful PDAC patients exhibited markedly increased mast cell infiltration in peritumoral tissues, but not in tumor tissues, along with elevated levels of CRF and mast cell-specific CRFR1 expression, compared to asymptomatic patients. Consistently, in orthotopic PDAC mice models, flow cytometry and immunofluorescence staining confirmed increased CRFR1 expression in mast cells. Both pharmacological inhibition of CRFR1 and mast cell specific CRFR1 knockout suppressed mast cell degranulation and alleviated cancer pain in male and female mice. Mechanistically, RNA sequencing, western blotting, and ELISA indicated that CRFR1 activated MAPK pathway signaling, upregulated SPHK1 expression, and increased S1P levels. A rescue experiment revealed that MAPK inhibition blocked CRFR1-induced SPHK1 upregulation in vitro. Importantly, the SPHK1 inhibitor PF543 reduced abdominal hyperalgesia in mice, while this effect was abolished in mast cell deficient mice. Moreover, SPHK1 knockdown by siRNA abolished CRFR1-induced mast cell degranulation. These findings highlight the critical role of mast cell CRFR1 in mediating abdominal hyperalgesia and identify the MAPK/SPHK1/S1P axis as an essential pathway, suggesting that targeting mast cell CRFR1 may be a promising therapeutic strategy for managing pancreatic cancer pain.

ORGANISM(S): Mus musculus

PROVIDER: GSE311236 | GEO | 2025/11/29

REPOSITORIES: GEO

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Project description:Background: Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. Sphingosine-1-phosphate (S1P) is a lipid mediator that regulates immune cell trafficking by signaling via five G protein-coupled receptors (S1PRs). We investigated the role of S1P in the RTM of aortic intimal MCs. Methods: Intravenous injection of lipopolysaccharide (LPS) was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. Results: In wild-type C57BL/6 mice, LPS induced intimal cell expression of S1pr1, S1pr3, and sphingosine kinase 1 (Sphk1, a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked LPS-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked LPS-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima and blunted LPS-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and LPS-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1 +/+ and -/- bone marrow. Stimulation with LPS increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. Conclusions: Functional and expression studies support a novel role for S1P signaling in the regulation of LPS-induced RTM as well as the homeostatic maintenance of aortic intimal MCs. Our data provides insight into how circulating plasma mediators help orchestrate intimal MC dynamics.

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Mast cell CRFR1 contributes to pancreatic cancer pain via MAPK/SPHK1 signaling

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