Conditional Deletion of the V-ATPase a2-Subunit Disrupts Intrathymic T Cell Development.

Proper orchestration of T lymphocyte development is critical, as T cells underlie nearly all responses of the adaptive immune system. Developing thymocytes differentiate in response to environmental cues carried from cell surface receptors to the nucleus, shaping a distinct transcriptional program that defines their developmental outcome. Our recent work has identified a previously undescribed role for the vacuolar ATPase (V-ATPase) in facilitating the development of murine thymocytes progressing toward the CD4 and CD8 αβ T cell lineages.

Surfactant protein A suppresses preterm delivery induced by live Escherichia coli in mice.

Preterm birth accounts for the majority of neonatal morbidity and mortality in the developed world. A significant proportion of cases of spontaneous preterm labor are attributable to infections within gestational tissues. Surfactant protein A (SP-A), a collectin produced in the fetal lung and other tissues, has been shown previously in mice to suppress preterm delivery due to intrauterine (IU) instillation of sterile proinflammatory substances.

Interleukin 22 prevents lipopolysaccharide- induced preterm labor in mice.

Preterm birth is widespread and causes 35% of all neonatal deaths. Infants who survive face potential long-term complications. A major contributing factor of preterm birth is infection.

Pregnancy is a model for tumors, not transplantation.

Nearly 65 years have passed since Peter Medawar posed the following question: "How does the pregnant mother contrive to nourish within itself, for many weeks or months, a fetus that is an antigenically foreign body." Now, understanding of reproductive immunology has demonstrated that the HLA antigens in the placenta are non-classical and do not induce rejection. In the placenta and in tumors, 50% or more of the cells are cells of the immune system and were once thought to be primed and ready for killing tumors or the "fetal transplant" but these cells are not potential killers but abet the growth of either the tumor or the placenta.

Depletion of H2S during obesity enhances store-operated Ca2+ entry in adipose tissue macrophages to increase cytokine production.

The increased production of proinflammatory cytokines by adipose tissue macrophages (ATMs) contributes to chronic, low-level inflammation during obesity. We found that obesity in mice reduced the bioavailability of the gaseous signaling molecule hydrogen sulfide (H2S). Steady-state, intracellular concentrations of H2S were lower in ATMs isolated from mice with diet-induced obesity than in ATMs from lean mice.

Notch Signaling in Inflammation-Induced Preterm Labor.

Notch signaling plays an important role in regulation of innate immune responses and trophoblast function during pregnancy. To identify the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligands (DLL (Delta-like protein)-1/3/4), Jagged 1/2) and Notch-induced transcription factor Hes1 were assessed during preterm labor. Preterm labor was initiated on gestation day 14.

Breast cancer associated a2 isoform vacuolar ATPase immunomodulates neutrophils: potential role in tumor progression.

In invasive breast cancer, tumor associated neutrophils (TAN) represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing ideal immunotherapies. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells.

The Vacuolar ATPase a2-subunit regulates Notch signaling in triple-negative breast cancer cells.

Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer with poor prognosis for which no targeted therapies are currently available. Notch signaling has been implicated in breast cancer but the factors that control Notch in TNBC are unknown. Because the Vacuolar ATPase has been shown to be important in breast cancer invasiveness, we investigated the role of a2-subunit isoform of Vacuolar ATPase (a2V) in regulating Notch signaling in TNBC.

Role of Notch signaling during lipopolysaccharide-induced preterm labor.

Notch signaling pathways exert effects throughout pregnancy and are activated in response to TLR ligands. To investigate the role of Notch signaling in preterm labor, Notch receptors (Notch1-4), its ligand Delta-like protein-1, transcriptional repressor hairy and enhancer of split-1, and Notch deregulator Numb were assessed. Preterm labor was initiated on gestation d 14.

Male fertility and apoptosis in normal spermatogenesis are regulated by vacuolar-ATPase isoform a2.

The a2 isoform of vacuolar-ATPase (ATP6V0A2, referred to as a2V) is required for normal spermatogenesis and maturation of sperm. Treatment of male mice with anti-a2V disturbs the testicular cytokine/chemokine balance and leads to severe deficiencies of spermatogenesis. The aim of the present study was to investigate the role of a2V in male fertility and in the regulation of apoptotic pathways required for normal spermatogenesis in mice.

Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor.

Cellular organelles and proteins are degraded and recycled through autophagy, a process during which vesicles known as autophagosomes fuse with lysosomes. Altered autophagy occurs in various diseases, but its role in preterm labor (PTL) is unknown. We investigated the role of autophagic flux in two mouse models of PTL compared to controls: 1) inflammation-induced PTL (IPTL), induced by toll-like receptor agonists; and 2) non-inflammation (hormonally)-induced PTL (NIPTL).

Vacuolar ATPase 'a2' isoform exhibits distinct cell surface accumulation and modulates matrix metalloproteinase activity in ovarian cancer.

Tumor associated vacuolar H+-ATPases (V-ATPases) are multi-subunit proton pumps that acidify tumor microenvironment, thereby promoting tumor invasion. Subunit 'a' of its V0 domain is the major pH sensing unit that additionally controls sub-cellular targeting of V-ATPase and exists in four different isoforms. Our study reports an elevated expression of the V-ATPase-V0a2 isoform in ovarian cancer(OVCA) tissues and cell lines(A2780, SKOV-3 and TOV-112D).

Platelet-activating factor: a role in preterm delivery and an essential interaction with Toll-like receptor signaling in mice.

Platelet-activating factor (PAF), a potent phospholipid activator of inflammation that signals through its cognate receptor (platelet-activating factor receptor, PTAFR), has been shown to induce preterm delivery in mice. Toll-like receptors (TLRs) are transmembrane receptors that mediate innate immunity. We have shown previously that Escherichia coli-induced preterm delivery in mice requires TLR signaling via the adaptor protein myeloid differentiation primary response gene 88 (MyD88), but not an alternative adaptor, Toll/IL-1 receptor domain-containing adapter protein-inducing interferon-beta (TRIF).

Future directions of clinical laboratory evaluation of pregnancy.

In recent years, our understanding of how the immune system interacts with the developing fetus and placenta has greatly expanded. There are many laboratories that provide tests for diagnosis of pregnancy outcome in women who have recurrent pregnancy loss (RPL) or pre-eclampsia. These tests are based on the premise that immune response to the fetus is equivalent to the adaptive immune response to a transplant.

Vacuolar-ATPase isoform a2 regulates macrophages and cytokine profile necessary for normal spermatogenesis in testis.

a2V is required for maturation of sperm. The decreased expression of a2V at the feto-maternal interphase causes poor pregnancy outcome. The present study examined the role of a2V in spermatogenesis and inflammatory network in the testis.

Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor.

An innate immune response is required for successful implantation and placentation. This is regulated, in part, by the a2 isoform of V-ATPase (a2V) and the concurrent infiltration of M1 (inflammatory) and M2 (anti-inflammatory) macrophages to the uterus and placenta. The objective of the present study was to identify the role of a2V during inflammation-induced preterm labor in mice and its relationship to the regulation of apoptosis and innate immune responses.

Expression of a2 vacuolar ATPase in spermatozoa is associated with semen quality and chemokine-cytokine profiles in infertile men.

Background: A number of laboratory tests have been developed to determine properties of spermatozoa quality but few have been adopted into routine clinical use in place of the WHO semen analysis. We investigated whether Atp6v0a2 (a2 isoform of vacuolar ATPase) is associated with abnormal semen quality and changes in chemokine-cytokine profiles in infertile men.

Patients And Methods: Semen samples were collected from 35 healthy donors and 35 infertile men at the Andrology laboratory from August 2011 to June 2012.

Lipopolysaccharide drives alternation of heat shock proteins and induces failure of blastocyst implantation in mouse.

The objective of the present study is to investigate the role of heat shock proteins (Hsps) in preimplantation embryonic development and uterine receptivity during lipopolysaccharide (LPS)-induced pregnancy loss. Mice were treated with PBS or LPS on Day 0.5 of pregnancy, and preimplantation embryos and uterus were collected on Days 1.

Lipopolysaccharide-induced modulation in the expression of progesterone receptor and estradiol receptor leads to early pregnancy loss in mouse.

The objective of the present study was to investigate the effect of Gram-negative bacteria infection on ovarian steroid receptors, i.e. progesterone receptor (PR) and estradiol receptor (ER) during preimplantation days of pregnancy.

V-ATPase upregulation during early pregnancy: a possible link to establishment of an inflammatory response during preimplantation period of pregnancy.

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.

Immune etiology of recurrent pregnancy loss and its diagnosis.

Recurrent Spontaneous Abortion of Immunological Origin (RSAI) is currently diagnosed by the occurrence of 2-3 consecutive miscarriages of unknown origin. The psychological trauma incurred by these events is a serious ailment which may be potentially avoided if a method of analysis is derived which may forecast these events and in turn prevent them from occurring. This review intends to examine studies of recurrent spontaneous abortion (RSA) which use laboratory diagnosis and also studies of RSA that do not use laboratory diagnosis.

Abortion-prone mating influences alteration of systemic a2 vacuolar ATPase expression in spleen and blood immune cells.

Problem: a2 isoform of vacuolar ATPase (Atp6v0a2) is important for maintaining the delicate immunological balance required for successful pregnancy. The objective of this investigation is to study the dynamic changes in spleen and blood that appear during spontaneous abortion in mice.

Method Of Study: Atp6v0a2 was measured in multiple immune cell populations from spleen and blood recovered from non-abortion-prone and abortion-prone mating combinations.