Chronic pelvic pain syndrome (CPPS), is a multi-symptom syndrome with unknown etiology. The experimental autoimmune prostatitis (EAP) mouse model of CPPS 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. CCL2 immunoreactivity was elevated to a similar degree in the DRG at day 14 and day 28. D14 of EAP was associated with elevated IBA1 cells in the DRG that were not evident at D28. Adoptive transfer of GFP+ leukocytes into EAP mice demonstrated monocytes are capable of infiltrating the spinal cord from peripheral blood with what appeared 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 two cell types suggesting cell-cell interactions. Lastly, intrathecal administration of liposomal clodronate ameliorated pelvic pain symptoms, suggesting a mechanistic role for macrophages and microglia in chronic pelvic pain.
Pain. 2020 Jun 10 [Epub ahead of print]
Zhiqiang Liu, Stephen F Murphy, Larry Wong, Anthony J Schaeffer, Praveen Thumbikat
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, United States.