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Neuronal/astrocytic expression of chemokine (C-C motif) ligand 2 is associated with monocyte/macrophage recruitment in male chronic pelvic pain.

ABSTRACT: Chronic pelvic pain syndrome is a multisymptom syndrome with unknown etiology. The experimental autoimmune prostatitis (EAP) mouse model of chronic pelvic pain syndrome is associated with immune cell infiltration into the prostate, expression of C-C chemokine ligand 2 (CCL2), and neuroinflammation in the spinal cord. Here, we studied CCL2 expression in tissues along the nociceptive pathway and its association with neuroimmune cells during pain development. Examination of prostate tissues at days 14 and 28 after EAP induction revealed CCL2 expression was increased in epithelial cells and was associated with increased numbers of macrophages lying in close apposition to PGP9.5-positive afferent neuronal fibers. C-C Chemokine ligand 2 immunoreactivity was elevated to a similar degree in the dorsal root ganglia at day 14 and day 28. D14 of EAP was associated with elevated IBA1 cells in the dorsal root ganglia that were not evident at D28. Adoptive transfer of green fluorescent protein+ leukocytes into EAP mice demonstrated monocytes are capable of infiltrating the spinal cord from peripheral blood with what seemed to be a proinflammatory phenotype. In the lower dorsal spinal cord, CCL2 expression localized to NeuN expressing neurons and GFAP-expressing astrocytes. Myeloid derived cell infiltration into the spinal cord in EAP was observed in the L6-S2 dorsal horn. Myeloid-derived CD45 IBA1+ cells were localized with IBA1+ TMEM199+ microglia in the dorsal horn of the spinal cord in EAP, with intimate association of the 2 cell types suggesting cell-cell interactions. Finally, intrathecal administration of liposomal clodronate ameliorated pelvic pain symptoms, suggesting a mechanistic role for macrophages and microglia in chronic pelvic pain.

SUBMITTER: Liu Z

PROVIDER: S-EPMC7572547 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and aimsHepatocellular carcinoma (HCC) is an aggressive malignancy which is often associated with a complex tumor microenvironment attributable to etiology-induced cellular inflammation. γδ T cells are known to detect and react to chronic inflammation, which is linked to cancer development, progression, and metastasis. Our recent genomic study revealed an increased infiltration of several immune cell types, including γδ T cells, in tumor microenvironments of a Thai HCC subtype associated with a good prognosis.Approach and resultsHere, we quantified the amount of γδ T cells using a γδ T-cell-specific gene signature in 247 Chinese HCC patients. We also validated the γδ T-cell signature in American HCC patients. Additionally, such an association was only found in tumor transcriptomic data, but not in adjacent nontumor transcriptomic data, suggesting a selective enrichment of γδ T cells in the tumor microenvironment. Moreover, the γδ T-cell signature was positively correlated with the expression of natural killer cell receptor genes, such as NKG2D and cytolytic T-cell genes granzymes and perforin, suggesting a stronger T-cell-mediated cytotoxic activity. Furthermore, we found that the γδ T-cell-specific gene expression is positively correlated with the expression of chemokine (C-C motif) ligand 4 (CCL4)/chemokine (C-C motif) ligand 5 (CCL5) and C-C chemokine receptor type 1 (CCR1)/C-C chemokine receptor type 5 (CCR5), the receptors for γδ T cells. We validated these results using immunohistochemical analysis of formalin-fixed, paraffin-embedded tumor biopsies from 182 HCC patients. Moreover, we found evidence of CCL4/CCL5-mediated recruitment of γδ T cells both in vitro and in a murine orthotopic Hepa1-6 HCC model.ConclusionsWe propose that CCL4/CCL5 may interact with their receptor, CCR1/CCR5, which may facilitate the recruitment of γδ T cells from peripheral blood or peritumor regions to the tumor regions. Consequently, an increasing infiltration of γδ T cells in tumors may enhance antitumor immunity and improve patients' prognosis.

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Neuronal/astrocytic expression of chemokine (C-C motif) ligand 2 is associated with monocyte/macrophage recruitment in male chronic pelvic pain.

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