title: V-ATPase upregulation during early pregnancy: a possible link to establishment of an inflammatory response during preimplantation period of pregnancy.
abstract: Various mechanisms exist to prevent a potentially deleterious maternal immune response that results in compromising survival of semiallogeneic fetus. In pregnancy, there is a necessary early preimplantation inflammatory stage followed by a postimplantation anti-inflammatory stage. Thus, there is a biphasic 'immune response' observed during the course of pregnancy. We provide the evidence that capacitation of sperm induced the expression of a2 isoform of V-ATPase (ATP6V0A2 referred to as a2V), leukemia inhibitory factor (Lif), Il1b, and Tnf in the sperm. Capacitated sperm also released cleaved N-terminal domain of a2V-ATPase (a2NTD), which upregulates the gene expression of Lif, Il1b, Tnf, and monocyte chemotactic protein-1 (Ccl2 (Mcp1)) in the uterus. Unfertilized eggs had low a2V expression, but after fertilization, the expression of a2V increased in zygotes. This increased level of a2V expression was maintained in preimplantation embryos. Seminal plasma was necessary for upregulation of a2V expression in preimplantation embryos, as mating with seminal vesicle-deficient males failed to elicit an increase in a2V expression in preimplantation embryos. The infiltration of macrophages into the uterus was significantly increased after insemination of both sperm and seminal plasma during the preimplantation period of pregnancy. This dynamic infiltration into the uterus corresponded with the uterine a2V expression through the induction of Ccl2 expression. Furthermore, the polarization ratio of M1:M2 (pro-inflammatory/anti-inflammatory) macrophages in the uterus fluctuated from a ratio of 1.60 (day 1) to 1.45 (day 4) when female mice were inseminated with both sperm and seminal plasma. These data provide evidence that exposure to semen may initiate an inflammatory milieu by inducing a2V and cytokine/chemokine expression, which triggers the influx of macrophages into the preimplantation uterus during the onset of pregnancy and ultimately leads to successful pregnancy outcome.
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jaiswal
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Mallers
authors.forename: Benjamin
authors.initials: B
authors.lastname: Larsen
authors.forename: Joanne
authors.initials: J
authors.lastname: Kwak-Kim
authors.forename: Gerard
authors.initials: G
authors.lastname: Chaouat
authors.forename: Alice
authors.initials: A
authors.lastname: Gilman-Sachs
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Beaman
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000201:enzymology* / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D005306:Fertilization; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D007315:Insemination, Artificial; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D006180:Proton-Translocating ATPases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D012669:Seminal Vesicles / Q000601:surgery; D013075:Sperm Capacitation; D013094:Spermatozoa / Q000201:enzymology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014599:Uterus / Q000201:enzymology* / Q000276:immunology; D014649:Vas Deferens / Q000601:surgery; D014659:Vasectomy
chemical_list: C432920:Atp6v0a2 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C092119:Hoxa10 protein, mouse; D006180:Proton-Translocating ATPases