{"paper_id":"a0c882a7-8bff-4b4e-ac49-6b54f5674b14","body_text":"Abstract\nEndometriosis is a chronic inflammatory disease and one of the most common causes of pelvic pain. The mechanisms underlying pain emergence or chronic inflammation during endometriosis remain unknown. Several chronic inflammatory diseases including endometriosis show reduced amounts of noradrenergic nerve fibers. The source of the affected innervation is still unclear. Semaphorins represent potential elicitors, due to their known role as axonal guidance cues, and are suggested as nerve repellent factors in different chronic inflammatory diseases. Therefore, semaphorins might influence the progress of neuroinflammatory mechanisms during endometriosis. Here, we analyzed the noradrenergic innervation and the expression of the specific semaphorins and receptors possibly involved in the neuroimmunomodulation in endometriosis. Our studies revealed an affected innervation and a significant increase of semaphorins and their receptors in peritoneal endometriotic tissue. Thereby, the expression of the receptors was identified on the membrane of noradrenergic nerve fibers and vessels. Macrophages and activated fibroblasts were found in higher density levels and additionally express semaphorins in peritoneal endometriotic tissue. Inflammation leads to an increased release of immune cells, which secrete a variety of inflammatory factors capable of affecting innervation. Therefore, our data suggests that the chronic inflammatory condition in endometriosis might contribute to the increase of semaphorins, which could possibly affect the innervation in peritoneal endometriosis.\nSimilar content being viewed by others\nReferences\nVigano P, Parazzini F, Somigliana E, Vercellini P (2004) Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol 18:177–200\nStraub RH, Bijlsma JW, Masi A, Cutolo M (2013) Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases—the 10-year update. Semin Arthritis Rheum 43:392–404\nCapellino S, Straub RH (2008) Neuroendocrine immune pathways in chronic arthritis. Best Pract Res Clin Rheumatol 22:285–297\nStraub RH (2007) Autoimmune disease and innervation. Brain Behav Immun 21:528–534\nTran LV, Tokushige N, Berbic M, Markham R, Fraser IS (2009) Macrophages and nerve fibres in peritoneal endometriosis. Hum Reprod 24:835–841\nMontagna P, Capellino S, Villaggio B, Remorgida V, Ragni N, Cutolo M, et al. (2008) Peritoneal fluid macrophages in endometriosis: correlation between the expression of estrogen receptors and inflammation. Fertil Steril 90:156–164\nKingery WS (2010) Role of neuropeptide, cytokine, and growth factor signaling in complex regional pain syndrome. Pain Med 11:1239–1250\nLakhan SE, Kirchgessner A (2010) Neuroinflammation in inflammatory bowel disease. J Neuroinflammation 7:37\nPongratz G, Melzer M, Straub RH (2012) The sympathetic nervous system stimulates anti-inflammatory B cells in collagen-type II-induced arthritis. Ann Rheum Dis 71:432–439\nKoopman FA, Stoof SP, Straub RH, Van Maanen MA, Vervoordeldonk MJ, Tak PP (2011) Restoring the balance of the autonomic nervous system as an innovative approach to the treatment of rheumatoid arthritis. Mol Med 17:937–948\nKoninckx PR, Kennedy SH, Barlow DH (1999) Pathogenesis of endometriosis: the role of peritoneal fluid. Gynecol Obstet Investig 47(Suppl 1):23–33\nMessersmith EK, Leonardo ED, Shatz CJ, Tessier-Lavigne M, Goodman CS, Kolodkin AL (1995) Semaphorin III can function as a selective chemorepellent to pattern sensory projections in the spinal cord. Neuron 14:949–959\nChedotal A, Del Rio JA, Ruiz M, He Z, Borrell V, de Castro F, et al. (1998) Semaphorins III and IV repel hippocampal axons via two distinct receptors. Development 125:4313–4323\nSteup A, Lohrum M, Hamscho N, Savaskan NE, Ninnemann O, Nitsch R, et al. (2000) Sema3C and netrin-1 differentially affect axon growth in the hippocampal formation. Mol Cell Neurosci 15:141–155\nStraub RH, Grum F, Strauch U, Capellino S, Bataille F, Bleich A, et al. (2008) Anti-inflammatory role of sympathetic nerves in chronic intestinal inflammation. Gut 57:911–921\nMiller LE, Weidler C, Falk W, Angele P, Schaumburger J, Scholmerich J, et al. (2004) Increased prevalence of semaphorin 3C, a repellent of sympathetic nerve fibers, in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 50:1156–1163\nJi JD, Park-Min KH, Ivashkiv LB (2009) Expression and function of semaphorin 3A and its receptors in human monocyte-derived macrophages. Hum Immunol 70:211–217\nPasterkamp RJ, Giger RJ, Ruitenberg MJ, Holtmaat AJ, De Wit J, De Winter F, et al. (1999) Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS. Mol Cell Neurosci 13:143–166\nBerkley KJ, Dmitrieva N, Curtis KS, Papka RE (2004) Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci U S A 101:11094–11098\nRicheri A, Chalar C, Martinez G, Greif G, Bianchimano P, Brauer MM (2011) Estrogen up-regulation of semaphorin 3F correlates with sympathetic denervation of the rat uterus. Auton Neurosci 164:43–50\nKlatt S, Fassold A, Straub RH (2012) Sympathetic nerve fiber repulsion: testing norepinephrine, dopamine, and 17 beta-estradiol in a primary murine sympathetic neurite outgrowth assay. Ann N Y Acad Sci 1261:26–33\nFassold A, Falk W, Anders S, Hirsch T, Mirsky VM, Straub RH (2009) Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritis. Arthritis Rheum 60:2892–2901\nGraf N, McLean M, Capellino S, Scholmerich J, Murray GI, El-Omar EM, et al. (2012) Loss of sensory and noradrenergic innervation in benign colorectal adenomatous polyps—a putative role of semaphorins 3F and 3 A. Neurogastroenterol Motil 24:120–128 e83\nGiger RJ, Pasterkamp RJ, Holtmaat AJ, Verhaagen J (1998) Semaphorin III: role in neuronal development and structural plasticity. Prog Brain Res 117:133–149\nChen H, Chedotal A, He Z, Goodman CS, Tessier-Lavigne M (1997) Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 19:547–559\nTakahashi T, Nakamura F, Jin Z, Kalb RG, Strittmatter SM (1998) Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. Nat Neurosci 1:487–493\nCheng HJ, Bagri A, Yaron A, Stein E, Pleasure SJ, Tessier-Lavigne M (2001) Plexin-A3 mediates semaphorin signaling and regulates the development of hippocampal axonal projections. Neuron 32:249–263\nWaimey KE, Huang PH, Chen M, Cheng HJ (2008) Plexin-A3 and plexin-A4 restrict the migration of sympathetic neurons but not their neural crest precursors. Dev Biol 315:448–458\nYaron A, Huang PH, Cheng HJ, Tessier-Lavigne M (2005) Differential requirement for plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 semaphorins. Neuron 45:513–523\nRuediger T, Zimmer G, Barchmann S, Castellani V, Bagnard D, Bolz J (2013) Integration of opposing semaphorin guidance cues in cortical axons. Cereb Cortex 23:604–614\nBlaess S, Bodea GO, Kabanova A, Chanet S, Mugniery E, Derouiche A, et al. (2011) Temporal-spatial changes in sonic hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei. Neural Dev 6:29\nFerrero S, Haas S, Remorgida V, Camerini G, Fulcheri E, Ragni N, et al. (2010) Loss of sympathetic nerve fibers in intestinal endometriosis. Fertil Steril 94:2817–2819\nFiore R, Puschel AW (2003) The function of semaphorins during nervous system development. Front Biosci : J Virtual Libr 8:s484–s499\nPuschel AW, Adams RH, Betz H (1995) Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension. Neuron 14:941–948\nKolodkin AL, Matthes DJ, Goodman CS (1993) The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell 75:1389–1399\nAdams RH, Betz H, Puschel AW (1996) A novel class of murine semaphorins with homology to thrombospondin is differentially expressed during early embryogenesis. Mech Dev 57:33–45\nPotiron V, Roche J (2005) Class 3 semaphorin signaling: the end of a dogma. Science’s STKE : signal transduction knowledge environment 2005;pe24\nMangasser-Stephan K, Dooley S, Welter C, Mutschler W, Hanselmann RG (1997) Identification of human semaphorin E gene expression in rheumatoid synovial cells by mRNA differential display. Biochem Biophys Res Commun 234:153–156\nEnzerink A, Vaheri A (2011) Fibroblast activation in vascular inflammation. J Thromb Haemost : JTH 9:619–626\nCapparuccia L, Tamagnone L (2009) Semaphorin signaling in cancer cells and in cells of the tumor microenvironment—two sides of a coin. J Cell Sci 122:1723–1736\nDe Winter F, Oudega M, Lankhorst AJ, Hamers FP, Blits B, Ruitenberg MJ, et al. (2002) Injury-induced class 3 semaphorin expression in the rat spinal cord. Exp Neurol 175:61–75\nFeiner L, Koppel AM, Kobayashi H, Raper JA (1997) Secreted chick semaphorins bind recombinant neuropilin with similar affinities but bind different subsets of neurons in situ. Neuron 19:539–545\nRenzi MJ, Feiner L, Koppel AM, Raper JA (1999) A dominant negative receptor for specific secreted semaphorins is generated by deleting an extracellular domain from neuropilin-1. J Neurosci 19:7870–7880\nSuto F, Ito K, Uemura M, Shimizu M, Shinkawa Y, Sanbo M, et al. (2005) Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. J Neurosci 25:3628–3637\nAcknowledgment\nThis work was supported by the German Research Foundation (DFG, ME3413/5-1).\nAuthor information\nAuthors and Affiliations\nCorresponding author\nEthics declarations\nConflict of Interest\nThe authors declare that they have no conflict of interest.\nRights and permissions\nAbout this article\nCite this article\nScheerer, C., Frangini, S., Chiantera, V. et al. Reduced Sympathetic Innervation in Endometriosis is Associated to Semaphorin 3C and 3F Expression. Mol Neurobiol 54, 5131–5141 (2017). https://doi.org/10.1007/s12035-016-0058-1\nReceived:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1007/s12035-016-0058-1","source_license":"CC0","license_restricted":false}