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Macrophages and dendritic cells in the post-testicular environment

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Abstract

Macrophages (MΦ) and dendritic cells (DCs) are heterogeneous families of functionally and developmentally related immune cells that play crucial roles in tissue homeostasis and the regulation of immune responses. During the past 5 years, immunologists have generated a considerable amount of data that challenge dogmas about the ontogeny and functions of these highly versatile cells. The male excurrent duct system plays a critical role in the establishment of fertility by allowing sperm maturation, transport and storage. In addition, it is challenged by pathogens and must establish a protective and tolerogenic environment for a continuous flow of autoantigenic spermatozoa. The post-testicular environment and, in particular, the epididymis contain an intricate network of DCs and MΦ; however, the immunophysiology of this intriguing and highly specialized mucosal system is poorly understood. This review summarizes the current trends in mouse MΦ and DC biology and speculates about their roles in the steady-state epididymis. Unraveling immune cell functions in the male reproductive tract is an essential prerequisite for the design of innovative strategies aimed at controlling male fertility and treating infertility.

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References

  • Abe K, Takano H, Ito T (1984) Microvasculature of the mouse epididymis, with special reference to fenestrated capillaries localized in the initial segment. Anat Rec 209:209–218

    Article  PubMed  CAS  Google Scholar 

  • Arrighi S (2014) Are the basal cells of the mammalian epididymis still an enigma? Reprod Fertil Dev 26:1061–1071

    Article  PubMed  CAS  Google Scholar 

  • Arrighi S, Romanello MG, Domeneghini C (1994) Ultrastructure of the epithelium that lines the ductuli efferentes in domestic equidae, with particular reference to spermatophagy. Acta Anat 149:174–184

    Article  PubMed  CAS  Google Scholar 

  • Bain CC, Bravo-Blas A, Scott CL, Gomez Perdiguero E, Geissmann F, Henri S, Malissen B, Osborne LC, Artis D, Mowat AM (2014) Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol 15:929–937

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Belleannee C, Thimon V, Sullivan R (2012) Region-specific gene expression in the epididymis. Cell Tissue Res 349:717–731

    Article  PubMed  Google Scholar 

  • Bjornson ZB, Nolan GP, Fantl WJ (2013) Single-cell mass cytometry for analysis of immune system functional states. Curr Opin Immunol 25:484–494

    Article  PubMed  CAS  Google Scholar 

  • Chang SY, Song JH, Guleng B, Cotoner CA, Arihiro S, Zhao Y, Chiang HS, O'Keeffe M, Liao G, Karp CL, Kweon MN, Sharpe AH, Bhan A, Terhorst C, Reinecker HC (2013) Circulatory antigen processing by mucosal dendritic cells controls CD8(+) T cell activation. Immunity 38:153–165

    Article  PubMed  CAS  Google Scholar 

  • Cooper TG (2015) Epididymal research: more warp than weft? Asian J Androl (in press)

  • Cooper TG, Yeung CH, Jones R, Orgebin-Crist MC, Robaire B (2002) Rebuttal of a role for the epididymis in sperm quality control by phagocytosis of defective sperm. J Cell Sci 115:5–7

    PubMed  CAS  Google Scholar 

  • Cornwall GA (2009) New insights into epididymal biology and function. Hum Reprod Update 15:213–227

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Da Silva N, Cortez-Retamozo V, Reinecker HC, Wildgruber M, Hill E, Brown D, Swirski FK, Pittet MJ, Breton S (2011) A dense network of dendritic cells populates the murine epididymis. Reproduction 141:653–663

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dacheux JL, Dacheux F (2014) New insights into epididymal function in relation to sperm maturation. Reproduction 147:R27–R42

    Article  PubMed  CAS  Google Scholar 

  • Davies LC, Jenkins SJ, Allen JE, Taylor PR (2013) Tissue-resident macrophages. Nat Immunol 14:986–995

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dorin JR, Barratt CL (2014) Importance of beta-defensins in sperm function. Mol Hum Reprod 20:821–826

    Article  PubMed  CAS  Google Scholar 

  • Dube E, Cyr DG (2012) The blood-epididymis barrier and human male fertility. Adv Exp Med Biol 763:218–236

    PubMed  CAS  Google Scholar 

  • Forrester JV, Xu H, Lambe T, Cornall R (2008) Immune privilege or privileged immunity? Mucosal Immunol 1:372–381

    Article  PubMed  CAS  Google Scholar 

  • Gerner MY, Kastenmuller W, Ifrim I, Kabat J, Germain RN (2012) Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes. Immunity 37:364–376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404

    Article  PubMed  CAS  Google Scholar 

  • Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, Bruijn MF de, Geissmann F, Rodewald HR (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551

  • Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ, Spann NJ, Stender JD, Chun HB, Garner H, Geissmann F, Glass CK (2014) Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159:1327–1340

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, Segura E, Tussiwand R, Yona S (2014) Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 14:571–578

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guiton R, Henry-Berger J, Drevet JR (2013) The immunobiology of the mammalian epididymis: the black box is now open! Basic Clin Androl 23:1–10

    Article  Google Scholar 

  • Hall SH, Yenugu S, Radhakrishnan Y, Avellar MC, Petrusz P, French FS (2007) Characterization and functions of beta defensins in the epididymis. Asian J Androl 9:453–462

    Article  PubMed  CAS  Google Scholar 

  • Haniffa M, Collin M, Ginhoux F (2013) Identification of human tissue cross-presenting dendritic cells: a new target for cancer vaccines. Oncoimmunology 2:e23140

    Article  PubMed  PubMed Central  Google Scholar 

  • Hedger MP (2011) Immunophysiology and pathology of inflammation in the testis and epididymis. J Androl 32:625–640

    Article  PubMed  CAS  Google Scholar 

  • Hedger MP, Hales DB (2006) Immunophysiology of the male reproductive tract. In: Neill JD (ed) Knobil and Neill's physiology of reproduction, vol 1. Elsevier Academic, Amsterdam, pp 1195–1286

    Chapter  Google Scholar 

  • Hermo L, Robaire B (2002) Epididymal cell types and thier functions. In: Robaire B, Hinton BT (eds) The epididymis: from molecular to clinical practice. A comprehensive survey of the efferent ducts, the epididymis and the vas deferens. Kluwer Academic/Plenum, New York, pp 81–102

  • Hirai S, Naito M, Terayama H, Ning Q, Miura M, Shirakami G, Itoh M (2010) Difference in abundance of blood and lymphatic capillaries in the murine epididymis. Med Mol Morphol 43:37–42

    Article  PubMed  Google Scholar 

  • Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P, Beaudin AE, Lum J, Low I, Forsberg EC, Poidinger M, Zolezzi F, Larbi A, Ng LG, Chan JK, Greter M, Becher B, Samokhvalov IM, Merad M, Ginhoux F (2015) C-myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42:665–678

    Article  PubMed  CAS  Google Scholar 

  • Holstein AF (1978) Spermatophagy in the seminiferous tubules and excurrent ducts of the testis in Rhesus monkey and in man. Andrologia 10:331–352

    Article  PubMed  CAS  Google Scholar 

  • Joffre OP, Segura E, Savina A, Amigorena S (2012) Cross-presentation by dendritic cells. Nat Rev Immunol 12:557–569

    Article  PubMed  CAS  Google Scholar 

  • Jones R (2004) Sperm survival versus degradation in the mammalian epididymis: a hypothesis. Biol Reprod 71:1405–1411

    Article  PubMed  CAS  Google Scholar 

  • Jrad-Lamine A, Henry-Berger J, Damon-Soubeyrand C, Saez F, Kocer A, Janny L, Pons-Rejraji H, Munn DH, Mellor AL, Gharbi N, Cadet R, Guiton R, Aitken RJ, Drevet JR (2013) Indoleamine 2,3-dioxygenase 1 (ido1) is involved in the control of mouse caput epididymis immune environment. PLoS One 8:e66494

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim B, Roy J, Shum WW, Da Silva N, Breton S (2015) Role of testicular luminal factors on basal cell elongation and proliferation in the mouse epididymis. Biol Reprod 92:9

    Article  PubMed  Google Scholar 

  • Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, Jung S, Amit I (2014) Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159:1312–1326

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000prime Rep 6:13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mazzini E, Massimiliano L, Penna G, Rescigno M (2014) Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1(+) macrophages to CD103(+) dendritic cells. Immunity 40:248–261

    Article  PubMed  CAS  Google Scholar 

  • McDole JR, Wheeler LW, McDonald KG, Wang B, Konjufca V, Knoop KA, Newberry RD, Miller MJ (2012) Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483:345–349

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mietens A, Tasch S, Stammler A, Konrad L, Feuerstacke C, Middendorff R (2014) Time-lapse imaging as a tool to investigate contractility of the epididymal duct—effects of cGMP signaling. PLoS One 9:e92603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mildner A, Jung S (2014) Development and function of dendritic cell subsets. Immunity 40:642–656

    Article  PubMed  CAS  Google Scholar 

  • Mital P, Hinton BT, Dufour JM (2011) The blood-testis and blood-epididymis barriers are more than just their tight junctions. Biol Reprod 84:851–858

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mullen TE Jr, Kiessling RL, Kiessling AA (2003) Tissue-specific populations of leukocytes in semen-producing organs of the normal, hemicastrated, and vasectomized mouse. AIDS Res Hum Retrovir 19:235–243

    Article  PubMed  Google Scholar 

  • Muller PA, Koscso B, Rajani GM, Stevanovic K, Berres ML, Hashimoto D, Mortha A, Leboeuf M, Li XM, Mucida D, Stanley ER, Dahan S, Margolis KG, Gershon MD, Merad M, Bogunovic M (2014) Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158:300–313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nashan D, Malorny U, Sorg C, Cooper T, Nieschlag E (1989) Immuno-competent cells in the murine epididymis. Int J Androl 12:85–94

    Article  PubMed  CAS  Google Scholar 

  • Niess JH, Reinecker HC (2006) Dendritic cells: the commanders-in-chief of mucosal immune defenses. Curr Opin Gastroenterol 22:354–360

    Article  PubMed  Google Scholar 

  • Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, Vyas JM, Boes M, Ploegh HL, Fox JG, Littman DR, Reinecker HC (2005) CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307:254–258

    Article  PubMed  CAS  Google Scholar 

  • Pollanen P, Cooper TG (1994) Immunology of the testicular excurrent ducts. J Reprod Immunol 26:167–216

    Article  PubMed  CAS  Google Scholar 

  • Redgrove KA, McLaughlin EA (2014) The role of the immune response in Chlamydia trachomatis infection of the male genital tract: a double-edged sword. Front Immunol 5:534

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V (2011a) Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol 29:163–183

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reizis B, Colonna M, Trinchieri G, Barrat F, Gilliet M (2011b) Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system? Nat Rev Immunol 11:558–565

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Robaire B, Hermo L (1988) Efferent ducts, epididymis, and vas deferens: structure, functions, and their regulation. In: Knobil E, Neill J (eds) The physiology of reproduction, vol 1, 2nd edn. Raven, New York, 99–1080

  • Robaire B, Hinton BT (2002) The epididymis: from molecular to clinical practice. A comprehensive survey of the efferent ducts, the epididymis and the vas deferens. Kluwer Academic/Plenum, New York

    Book  Google Scholar 

  • Robaire B, Hinton BT, Orgebin-Crist MC (2006) The epididymis. In: Neill JD (ed) Knobil and Neill's physiology of reproduction, vol 1. Elsevier Academic, Amsterdam, pp 1072–1148

    Google Scholar 

  • Seiler P, Wenzel I, Wagenfeld A, Yeung CH, Nieschlag E, Cooper TG (1998) The appearance of basal cells in the developing murine epididymis and their temporal expression of macrophage antigens. Int J Androl 21:217–226

    Article  PubMed  CAS  Google Scholar 

  • Seiler P, Cooper TG, Yeung CH, Nieschlag E (1999) Regional variation in macrophage antigen expression by murine epididymal basal cells and their regulation by testicular factors. J Androl 20:738–746

    PubMed  CAS  Google Scholar 

  • Seiler P, Cooper TG, Nieschlag E (2000) Sperm number and condition affect the number of basal cells and their expression of macrophage antigen in the murine epididymis. Int J Androl 23:65–76

    Article  PubMed  CAS  Google Scholar 

  • Serre V, Robaire B (1999) Distribution of immune cells in the epididymis of the aging brown Norway rat is segment-specific and related to the luminal content. Biol Reprod 61:705–714

    Article  PubMed  CAS  Google Scholar 

  • Serre V, Robaire B (2002) Interactions of the immune system and the epididymis. In: Robaire B, Hinton BT (eds) The epididymis: from molecular to clinical practice. A comprehensive survey of the efferent ducts, the epididymis and the vas deferens, vol 1. Kluwer Academic/Plenum, New York, pp 219–231

    Google Scholar 

  • Shum WW, Da Silva N, Brown D, Breton S (2009) Regulation of luminal acidification in the male reproductive tract via cell-cell crosstalk. J Exp Biol 212:1753–1761

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shum WW, Ruan YC, Da Silva N, Breton S (2011) Establishment of cell-cell cross talk in the epididymis: control of luminal acidification. J Androl 32:576–586

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shum WW, Smith TB, Cortez-Retamozo V, Grigoryeva LS, Roy JW, Hill E, Pittet MJ, Breton S, Da Silva N (2014) Epithelial basal cells are distinct from dendritic cells and macrophages in the mouse epididymis. Biol Reprod 90:90

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Smith TB, Cortez-Retamozo V, Grigoryeva LS, Hill E, Pittet MJ, Da Silva N (2014) Mononuclear phagocytes rapidly clear apoptotic epithelial cells in the proximal epididymis. Andrology 2:755–762

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Smith T, Courties G, Barton C, Nahrendorf M, Da Silva N (2015) Macrophages and dendritic cells cooperate to survey the epididymal lumen. In: Rajpert-DeMayts E, Carrell T (eds) Andrology. Handbook from the American Society of Andrology meeting, 18–21 April 2015, Salt Lake City, USA. American Society of Andrology, Schaumburg, Suppl p 46

    Google Scholar 

  • Sutovsky P (2003) Ubiquitin-dependent proteolysis in mammalian spermatogenesis, fertilization, and sperm quality control: killing three birds with one stone. Microsc Res Tech 61:88–102

    Article  PubMed  CAS  Google Scholar 

  • Sutovsky P, Moreno R, Ramalho-Santos J, Dominko T, Thompson WE, Schatten G (2001) A putative, ubiquitin-dependent mechanism for the recognition and elimination of defective spermatozoa in the mammalian epididymis. J Cell Sci 114:1665–1675

    PubMed  CAS  Google Scholar 

  • Sutovsky P, Neuber E, Schatten G (2002) Ubiquitin-dependent sperm quality control mechanism recognizes spermatozoa with DNA defects as revealed by dual ubiquitin-TUNEL assay. Mol Reprod Dev 61:406–413

    Article  PubMed  CAS  Google Scholar 

  • Suzuki F (1982) Microvasculature of the mouse testis and excurrent duct system. Am J Anat 163:309–325

    Article  PubMed  CAS  Google Scholar 

  • Turner TT (1995) On the epididymis and its role in the development of the fertile ejaculate. J Androl 16:292–298

    PubMed  CAS  Google Scholar 

  • Turner TT, Riley TA (1999) p53 independent, region-specific epithelial apoptosis is induced in the rat epididymis by deprivation of luminal factors. Mol Reprod Dev 53:188–197

    Article  PubMed  CAS  Google Scholar 

  • Turner TT, Johnston DS, Finger JN, Jelinsky SA (2007) Differential gene expression among the proximal segments of the rat epididymis is lost after efferent duct ligation. Biol Reprod 77:165–171

    Article  PubMed  CAS  Google Scholar 

  • Yeung CH, Nashan D, Sorg C, Oberpenning F, Schulze H, Nieschlag E, Cooper TG (1994) Basal cells of the human epididymis—antigenic and ultrastructural similarities to tissue-fixed macrophages. Biol Reprod 50:917–926

    Article  PubMed  CAS  Google Scholar 

  • Yeung CH, Wang K, Cooper TG (2012) Why are epididymal tumours so rare? Asian J Androl 14:465–475

    Article  PubMed  PubMed Central  Google Scholar 

  • Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38:79–91

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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  1. Division of Nephrology, Center for Systems Biology and Program in Membrane Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, 185 Cambridge Street, CPZN 8.218, Boston, MA 02114-2790, USA

    Nicolas Da Silva & Claire R. Barton

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Correspondence to Nicolas Da Silva.

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Da Silva, N., Barton, C.R. Macrophages and dendritic cells in the post-testicular environment. Cell Tissue Res 363, 97–104 (2016). https://doi.org/10.1007/s00441-015-2270-0

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