Mast Cell-Derived CCL2 Exacerbates Endometriosis Pain via Binding to CCR4

Ya Deng, Chen P, Ping Chen, Ding H, Haigang Ding
Omics : a journal of integrative biology · 2026 · pp. 15578100261503774 · doi:10.1177/15578100261503774 · PMID:42992652 · W7225422000
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Mast cell-derived CCL2 exacerbates endometriosis pain by activating neuronal CCR4, as demonstrated through patient tissue analysis, in vitro cocultures, and rat models showing that inhibiting this pathway relieves hyperalgesia.

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Abstract

Endometriosis (EMs) pain severely reduces patients' quality of life, but its underlying mechanisms are not fully understood. Mast cells and C-C motif chemokine ligand 2 (CCL2) are highly abundant in EMs lesions, yet their roles in neural sensitization remain unclear. Bioinformatics analysis of a public scRNA-seq dataset (GSE179640) was performed to define CCL2 expression across EMs cell types and its enrichment in mast cells. We collected ectopic and eutopic endometrial tissues from EMs patients and normal endometrial tissues from controls. CCL2, C-C chemokine receptor type 4 (CCR4) expression, mast cell numbers, and protein gene product 9.5-positive nerve fibers were measured and correlated with pain. In vitro coculture models of endometrial stromal cells, mast cells, and neurons were established, and related functions were examined. An in vivo EMs rat model was used to assess pain thresholds and nerve fiber density. CCL2 was significantly upregulated in EMs and positively correlated with pain, mast cell infiltration, and sensory nerves. Stromal cell-mast cell coculture increased CCL2. CCL2 knockdown in mast cells inhibited degranulation and migration but promoted neurite outgrowth, nerve growth factor expression, and calcium influx in neurons. Inhibiting CCR4 relieved hyperalgesia and reduced lesion nerve fibers in rats. Mast cell-derived CCL2 promotes neural sensitization by activating neuronal CCR4, which contributes to EMs pain. Targeting CCL2/CCR4 may serve as a new therapeutic approach for EMs pain.

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