CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis.
Experimental autoimmune prostatitis (EAP) is a murine model of chronic prostatitis/chronic pelvic pain syndrome (CPPS) in men, a syndrome characterized by chronic pelvic pain. We have demonstrated that chemokine ligands CCL2 and CCL3 are biomarkers that correlate with pelvic pain symptoms. We postulated that CCL2 and CCL3 play a functional role in CPPS and therefore examined their expression in EAP. Upon examination of the prostate 5 days after induction of EAP, CCL2 mRNA was elevated 2- to 3-fold, CCL8 by 15-fold, CCL12 by 12- to 13-fold, and CXCL9 by 2- to 4-fold compared with control mice. At 10 days the major chemokines were CXCL13 and CXCL2; at 20 days CCL2 (1- to 2-fold), CCL3 (2- to 3-fold) and CCL11 (2- to 3-fold); and at 30 days, CCL12 (20- to 35-fold) and smaller increases in CCL2, CCL3, and XCL1. Chemokine elevations were accompanied by increases in mast cells and B cells at 5 days, monocytes and neutrophils at day 10, CD4+ T cells at day 20, and CD4+ and CD8+ T cells at day 30. Anti-CCL2 and anti-CCL3 neutralizing antibodies administered at EAP onset attenuated pelvic pain development, but only anti-CCL2 antibodies were effective therapeutically. CCL2- and its cognate receptor CCR2-deficient mice were completely protected from development of pain symptoms but assumed susceptibility after reconstitution with wild-type bone marrow. CCL3-deficient mice showed resistance to the maintenance of pelvic pain while CCR5-deficient mice did not show any lessening of pelvic pain severity. These results suggest that the CCL2-CCR2 axis and CCL3 are important mediators of chronic pelvic pain in EAP.
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Marsha L
ML
Quick
Soumi
S
Mukherjee
Charles N
CN
Rudick
Joseph D
JD
Done
Anthony J
AJ
Schaeffer
Praveen
P
Thumbikat
D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism*; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D002908:Chronic Disease; D005786:Gene Expression Regulation / Q000502:physiology*; D007249:Inflammation / Q000473:pathology; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010146:Pain / Q000378:metabolism*; D011467:Prostate / Q000166:cytology / Q000473:pathology; D011472:Prostatitis / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054390:Receptors, CCR2; D019713:Receptors, CCR5