M1 Macrophages Are Predominantly Recruited to the Major Pelvic Ganglion of the Rat Following Cavernous Nerve Injury |
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| Institution: | 1. The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD, USA;2. Department of Urology, The University of Tokyo, Tokyo, Japan;3. Department of Urology, Doai Memorial Hospital, Tokyo, Japan;4. Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA;5. Department of Chemistry, Ripon College, Ripon, WI, USA;6. Laboratory for Experimental Urology, Department of Development and Regeneration, University of Leuven, Leuven, Belgium;7. Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden;1. Department of Obstetrics and Gynecology, Kochi Medical School, Kochi, Japan;2. Department of Pathology, Kochi Medical School, Kochi, Japan;1. Department of Anesthesia and Intensive Care Medicine, Tübingen University Hospital, Faculty of Medicine, Eberhard-Karls University Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany;1. Department of Reproductive Medicine, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, Guangdong, People''s Republic of China;2. Department of Urology, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangzhou, Guangdong, People''s Republic of China;3. Department of Urology, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People''s Republic of China;1. Department of Surgery, University of California–San Diego and San Diego VA Healthcare System, San Diego, CA, USA;2. Department of Anesthesiology, University of California–San Diego and San Diego VA Healthcare System, San Diego, CA, USA;3. Department of Internal Medicine, University of California–San Diego and San Diego VA Healthcare System, San Diego, CA, USA;4. Virginia Commonwealth University, Richmond, VA, USA;1. Lung Biology Group, Regenerative Medicine Institute, National University of Ireland, Galway, Ireland;2. Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland;3. Department of Anaesthesia, Keenan Research Centre for Biomedical Science, St Michael''s Hospital, University of Toronto, Toronto, Canada;1. Neuroimmunology Group, Molecular Drug Metabolism and Toxicology Laboratory, Department of Biochemistry, University of Ibadan, Ibadan, Nigeria;2. Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec, QC, Canada;3. Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos State, Nigeria;4. Faculté de pharmacie, Université Laval, Québec, QC, Canada;5. Département de médecine moléculaire, Faculté de médecine, Université Laval, Québec, QC, Canada;6. Division of Medical Sciences, University of Victoria, Victoria, BC, Canada |
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| Abstract: | IntroductionNeurogenic erectile dysfunction is a common sequela of radical prostatectomy. The etiology involves injury to the autonomic cavernous nerves, which arise from the major pelvic ganglion (MPG), and subsequent neuroinflammation, which leads to recruitment of macrophages to the injury site. Currently, two macrophage phenotypes are known: neurotoxic M1 macrophages and neuroprotective M2 macrophages.AimTo examine whether bilateral cavernous nerve injury (BCNI) in a rat model of erectile dysfunction would increase recruitment of neurotoxic M1 macrophages to the MPG.MethodsMale Sprague-Dawley rats underwent BCNI and the MPG was harvested at various time points after injury. The corpora cavernosa was used to evaluate tissue myographic responses to electrical field stimulation ex vivo. Quantitative real-time polymerase chain reaction was used to examine the gene expression of global macrophage markers, M1 macrophage markers, M2 macrophage markers, and cytokines and chemokines in the MPG. Mathematical calculation of the M1/M2 index was used to quantify macrophage changes temporally. Western blot of MPG tissues was used to evaluate the protein amount of M1 and M2 macrophage markers quantitatively. Immunohistochemistry staining of MPGs for CD68, CD86, and CD206 was used to characterize M1 and M2 macrophage infiltration.Main Outcome MeasuresCorpora cavernosa responsiveness ex vivo; gene (quantitative real-time polymerase chain reaction) and protein (western blot) expressions of M1 and M2 markers, cytokines, and chemokines; and immunohistochemical localization of M1 and M2 macrophages.ResultsBCNI impaired the corporal parasympathetic-mediated relaxation response to electrical field stimulation and enhanced the contraction response to electrical field stimulation. Gene expression of proinflammatory (Il1b, Il16, Tnfa, Tgfb, Ccl2, Ccr2) and anti-inflammatory (Il10) cytokines was upregulated in the MPG 48 hours after injury. M1 markers (CD86, inducible nitric oxide synthase, interleukin-1β) and M2 markers (CD206, arginase-1, interleukin-10) were increased after BCNI in the MPG, with the M1/M2 index above 1.0 indicating that more M1 than M2 macrophages were recruited to the MPG. Protein expression of the M1 macrophage marker (inducible nitric oxide synthase) was increased in MPGs after BCNI. However, the protein amount of M2 macrophage markers (arginase-1) remained unchanged. Immunohistochemical characterization demonstrated predominant increases in M1 (CD68+CD86+) macrophages in the MPG after BCNI.ConclusionThese results suggest that an increase in M1 macrophage infiltration of the MPG after BCNI is associated with impaired neurogenically mediated erectile tissue physiology ex vivo and thus has significant implications for cavernous nerve axonal repair. Future studies are needed to demonstrate that inhibition of M1 macrophage recruitment prevents erectile dysfunction after CNI. |
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| Keywords: | Peripheral Nerve Injury Neuroinflammation Macrophage Markers Neuroprotective Major Pelvic Ganglion Erectile Dysfunction |
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