Sphingolipid Pathway Regulates Innate Immune Responses at the Fetomaternal Interface during Pregnancy

Mizugishi, Kiyomi; Inoue, Takuya; Hatayama, Hiroshi; Bielawski, Jacek; Pierce, Jason S.; Sato, Yukiyasu; Takaori‐Kondo, Akifumi; Konishi, Ikuo; Yamashita, Kouhei

doi:10.1074/jbc.m114.628867

Cited by 32 publications

(33 citation statements)

References 52 publications

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“…Sphk1 2/2 Sphk2 +/2 female mice also exhibited neutrophilia in peripheral blood and enhanced granulocyte production in the bone marrow. Similar defects were observed in human decidual cells, and the secretion of CXCL1 and IL-8 was dramatically enhanced in Sphk-deficient human decidual cells (11). Together, these results suggest that neutrophils might be key players in Sphk-mediated pregnancy loss.…”

supporting

confidence: 71%

“…Studies using Sphk1 2/2 Sphk2 +/2 mice revealed that disrupting the sphingolipid metabolic pathway during pregnancy causes defects in decidualization characterized by the death of decidual cells and massive breakage of decidual blood vessels, and results in maternally derived early pregnancy loss (10). Detailed sphingolipid analysis revealed excessive accumulation of dihydrosphingosine and sphingosine in the decidua of pregnant Sphk1 2/2 Sphk2 +/2 female mice, while S1P levels were not significantly altered in Sphk1 2/2 Sphk2 +/2 decidua compared to wild-type (WT) decidua (10,11). Moreover, Sphk1 2/2 Sphk2 +/2 female mice demonstrated unusually high expression levels of the neutrophil chemoattractants CXCL1 and CXCL2 in the decidua.…”

mentioning

confidence: 99%

“…Moreover, Sphk1 2/2 Sphk2 +/2 female mice demonstrated unusually high expression levels of the neutrophil chemoattractants CXCL1 and CXCL2 in the decidua. These defects led to massive neutrophil infiltration into the fetomaternal interface and consequent maternally derived early pregnancy loss, and they were ameliorated by blocking neutrophil influx (11). Sphk1 2/2 Sphk2 +/2 female mice also exhibited neutrophilia in peripheral blood and enhanced granulocyte production in the bone marrow.…”

mentioning

confidence: 99%

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Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase–deficient mice on 129Sv/C57BL/6 background

Mizugishi¹,

Yamashita²

2017

The FASEB Journal

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Exaggerated maternal immune responses must be strictly controlled to ensure a successful pregnancy. Neutrophil extracellular traps (NETs) have recently been implicated as a potential mechanism for promoting inflammation in pregnancy-related disorders. In this study, we demonstrated that NETs play a key role in the pathogenesis of sphingosine kinase (Sphk)-mediated pregnancy loss. Perturbing the sphingolipid pathway by disrupting genes during pregnancy led to excessive NET formation exclusively at the fetomaternal interface and early fetal death. Neutrophils that formed NETs were characterized by histone hypercitrullination and peptidylarginine deiminase 4 (PAD4) overexpression. In addition, thrombus formation was enhanced in the decidua, but not in the plasma, of-deficient mice. Blocking NET formation with a PAD4 inhibitor protected -deficient mice from pregnancy loss. The PAD4 inhibition significantly reduced the expression of hypercitrullinated histone in neutrophils and ameliorated vascular injury in the decidua of-deficient mice. Moreover, NET formation was induced in human neutrophils stimulated with Sphk-deficient human decidual cells. Together, these findings indicate that targeting NETs might be a novel therapeutic strategy to treat idiopathic pregnancy loss in humans.-Mizugishi, K., Yamashita, K. Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase-deficient mice on 129Sv/C57BL/6 background.

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supporting

confidence: 71%

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confidence: 99%

mentioning

confidence: 99%

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Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase–deficient mice on 129Sv/C57BL/6 background

Mizugishi¹,

Yamashita²

2017

The FASEB Journal

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“…Increased levels of the chemokines CXCL1, CXCL2 and IL-8 in placental decidual cells of SK1 2/2 and SK2 2/2 mice have also been reported (Mizugishi et al, 2015), while prior studies have demonstrated increased levels of CXCL1, CXCL10, IL-8 and CCL20 in SK1 siRNA-treated cells (Adada et al, 2013). Thus, the literature supports a link between SK1 and basal levels of at least some chemokines, such as CXCL10, and the links we describe here between SK1 and basal levels of CXCL10, IRF7 and OAS1 in this SK1 2/2 iMEF line expand the potential interactions between SK1 and the host innate response.…”

Section: Discussionmentioning

confidence: 83%

Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses

Clarke

Davies

Calvert

et al. 2016

Journal of General Virology

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Sphingosine kinase (SK) 1 is a host kinase that enhances some viral infections. Here we investigated the ability of SK1 to modulate dengue virus (DENV) infection in vitro. Overexpression of SK1 did not alter DENV infection; however, targeting SK1 through chemical inhibition resulted in reduced DENV RNA and infectious virus release. DENV infection of SK1 2/2 murine embryonic fibroblasts (MEFs) resulted in inhibition of infection in an immortalized line (iMEF) but enhanced infection in primary MEFs (18MEFs). Global cellular gene expression profiles showed expected innate immune mRNA changes in DENV-infected WT but no induction of these responses in SK1 2/2 iMEFs. Reverse transciption PCR demonstrated a low-level induction of IFN-b and poor induction of mRNA for the interferon-stimulated genes (ISGs) viperin, IFIT1 and CXCL10 in DENV-infected SK1 2/2 compared with WT iMEFs. Similarly, reduced induction of ISGs was observed in SK1 2/2 18MEFs, even in the face of high-level DENV replication. In both iMEFs and 18MEFs, DENV infection induced production of IFN-b protein. Additionally, higher basal levels of antiviral factors (IRF7, CXCL10 and OAS1) were observed in uninfected SK1 2/2 iMEFs but not 18MEFs. This suggests that, in this single iMEF line, lack of SK1 upregulates the basal levels of factors that may protect cells against DENV infection. More importantly, regardless of the levels of DENV replication, all cells that lacked SK1 produced IFN-b but were refractory to induction of ISGs such as viperin, IFIT1 and CXCL10. Based on these findings, we propose new roles for SK1 in affecting innate responses that regulate susceptibility to DENV infection.

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“…Neutrophilia was also observed in SK1 deficient mice during pregnancy and correlated high levels of CXCL1 and CXCL2. This study however found that the combined loss of SK1 with heterozygocity of SK2 expression lead to increased neutrophil infiltrate into the fetomaternal interphase promoting oxidative damage and embryo death (Mizugishi et al, 2015). It remains to be answered how the S1P gradient in tissues could be altering neutrophil migration.…”

Section: Sphingolipids In Neutrophil Regulationmentioning

confidence: 84%

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

Espaillat

Kew

Obeid

2017

Advances in Biological Regulation

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Bioactive sphingolipids are regulators of immune cell function and play critical roles in inflammatory conditions including ulcerative colitis. As one of the major forms of inflammatory bowel disease, ulcerative colitis pathophysiology is characterized by an aberrant intestinal inflammatory response that persists causing chronic inflammation and tissue injury. Innate immune cells play an integral role in normal intestinal homeostasis but their dysregulation is thought to contribute to the pathogenesis of ulcerative colitis. In particular, neutrophils are key effector cells and are first line defenders against invading pathogens. While the activity of neutrophils in the intestinal mucosa is required for homeostasis, regulatory mechanisms are equally important to prevent unnecessary activation. In ulcerative colitis, unregulated neutrophil inflammatory mechanisms promote tissue injury and loss of homeostasis. Aberrant neutrophil function represents an early checkpoint in the detrimental cycle of chronic intestinal inflammation; thus, dissecting the mechanisms by which these cells are regulated both before and during disease is essential for understanding the pathogenesis of ulcerative colitis. We present an analysis of the role of sphingolipids in the regulation of neutrophil function and the implication of this relationship in ulcerative colitis.

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Sphingolipid Pathway Regulates Innate Immune Responses at the Fetomaternal Interface during Pregnancy

Cited by 32 publications

References 52 publications

Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase–deficient mice on 129Sv/C57BL/6 background

Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase–deficient mice on 129Sv/C57BL/6 background

Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

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