The Chemokine Receptor CCR2 Is Not Required for Successful Initiation of Labor in Mice1

Menzies, Fiona M.; Khan, Afroz; Nelson, Scott M.; Nibbs, Robert J. B.

doi:10.1095/biolreprod.111.094631

Cited by 14 publications

(5 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…reported that mice deficient in Ccl2 receptor CCR2 have normal parturition despite reduced monocytes trafficking into the uterus. This study supports the potential importance of myeloid cells in PP uterine involution rather than initiation of term labour [54]. …”

Section: Discussionsupporting

confidence: 87%

Myometrial immune cells contribute to term parturition, preterm labour and post‐partum involution in mice

Shynlova

Nedd-Roderique

et al. 2012

J Cellular Molecular Medi

131

136

View full text Add to dashboard Cite

This study aimed to determine the mechanism of uterine activation during labour, both term (TL) and preterm (PTL). We hypothesized that the peripheral leucocytes are recruited to uterine tissues by locally produced cytokines where they contribute to the initiation of parturition. Mouse uteri were collected (i) during gestation, TL and post-partum (PP), (ii) during PTL initiated by intrauterine infusion of LPS (125 μg) or (iii) injection of the progesterone receptor antagonist RU486 and analysed for multiple cytokine expression levels by real-time polymerase chain reaction (RT-PCR) and 23-plex Cytokine assay or enzymatically dispersed for assessment of immune cell populations. Markers of myeloid cell differentiation (Gr1, Neu7/4 and F4/80) were evaluated by FACS to define tissue macrophages (Macs), monocytes (M) and neutrophils (N) and by immunohistochemistry to detect tissue Macs and N. Our results indicate that: (1) Macs were elevated in mouse myometrium before TL (P < 0.05) followed by an increase in M and N; these changes were accompanied by an increase in multiple pro-inflammatory cytokines/chemokines genes. The expression of corresponding proteins increased PP. (2) TL and RU486-PTL models showed similar gene/protein expression profiles, (3) LPS-PTL was characterized by strong pro-inflammatory response and massive influx of N in myometrial tissues showing a pattern different from TL and RU486-PTL, (4) The PP period appears similar in all three models, with elevated myometrial cytokine levels and high infiltration of immune cells. We concluded that leucocytes infiltrate myometrium around the time of parturition implicating their potential role in labour activation (both term and preterm) and major role in PP uterine involution.

show abstract

Section: Discussionsupporting

confidence: 87%

Myometrial immune cells contribute to term parturition, preterm labour and post‐partum involution in mice

Shynlova

Nedd-Roderique

et al. 2012

J Cellular Molecular Medi

131

136

View full text Add to dashboard Cite

show abstract

“…We observed that intrauterine administration of LPS on day 17 of gestation increased mRNA expression of Ngp in the uterus, placenta, and fetal membranes within 6 h, and that this increased expression was coincident with a large neutrophil influx into the decidua in response to intrauterine LPS treatment, confirming a suggested role for neutrophils in infection-induced PTL. These data contrast to those of Menzies et al (32), who demonstrated that expression of Ngp remains unchanged in laboring compared with nonlaboring mouse uterus and provide further support for the theory that infection-induced PTL and term labor may occur via different mechanisms, with neutrophils playing a specific role in infection-associated PTL (16, 33). …”

Section: Discussionsupporting

confidence: 55%

Decidual Neutrophil Infiltration Is Not Required for Preterm Birth in a Mouse Model of Infection-Induced Preterm Labor

Rinaldi

Catalano

Wade

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Parturition is associated with a leukocyte influx into the intrauterine tissues; however, the exact role these leukocytes play in the onset of labor remains unclear. Neutrophil infiltration of the uteroplacental tissues has been particularly associated with infection-associated preterm labor (PTL) in both women and mouse models. In this study, we investigated the role of neutrophils in a mouse model of infection-induced PTL. Intrauterine administration of LPS on day 17 of gestation resulted in a 7-fold increase in the number of decidual neutrophils compared with control mice receiving PBS (p < 0.01; n = 8–11). We hypothesized that neutrophil influx is necessary for PTL and that neutrophil depletion would abolish preterm birth. To test this hypothesis, mice were depleted of neutrophils by treatment with anti–Gr-1, anti–Ly-6G, or the appropriate IgG control Ab on day 16 of gestation prior to LPS on day 17 (n = 6–7). Successful neutrophil depletion was confirmed by flow cytometry and immunohistochemistry. Neutrophil depletion with Gr-1 resulted in reduced uterine and placental Il-1β expression (p < 0.05). Neutrophil depletion with Ly-6G reduced uterine Il-1β and Tnf-α expression (p < 0.05). However, neutrophil depletion with either Ab did not delay LPS-induced preterm birth. Collectively, these data show that decidual neutrophil infiltration is not essential for the induction of infection-induced PTL in the mouse, but that neutrophils contribute to the LPS-induced inflammatory response of the uteroplacental tissues.

show abstract

“…Whether inhibition of a subset of chemokines would be sufficient to reduce decidual immune cell trafficking and suppress inflammation during PTL remains unknown. However, individual chemokine receptor knockout mice do not exhibit a dysfunctional labour phenotype [43], suggesting targeting multiple pathways may be necessary.…”

Section: Discussionmentioning

confidence: 99%

Identification of Chemokines Associated with the Recruitment of Decidual Leukocytes in Human Labour: Potential Novel Targets for Preterm Labour

2013

View full text Add to dashboard Cite

Current therapies for preterm labour (PTL) focus on arresting myometrial contractions but are largely ineffective, thus alternative therapeutic targets need to be identified. Leukocytes infiltrate the uterus around the time of labour, and are in particularly abundant in decidua (maternal-fetal interface). Moreover, decidual inflammation precedes labour in rat pregnancies and thus may contribute to initiation of labour. We hypothesized that chemokines mediate decidual leukocyte trafficking during preterm labour (PTL) and term labour (TL), thus representing potential targets for preventing PTL. Women were recruited into 4 groups: TL, term not in labour (TNL), idiopathic PTL and PTL with infection (PTLI). Choriodecidual RNA was subjected to a pathway-specific PCR array for chemokines. Differential expression of 12 candidate chemokines was validated by real time RT-PCR and Bioplex assay, with immunohistochemistry to confirm cellular origin. 25 chemokines were upregulated in choriodecidua from TL compared to TNL. A similar pattern was detected in PTL, however a distinct profile was observed in PTLI consistent with differences in leukocyte infiltration. Upregulation of CCL2, CCL4, CCL5, CXCL8 and CXCL10 mRNA and protein was confirmed in TL, with CCL8 upregulated in PTL. Significant correlations were detected between these chemokines and decidual leukocyte abundance previously assessed by immunohistochemical and image analysis. Chemokines were primarily expressed by decidual stromal cells. In addition, CXCL8 and CCL5 were significantly elevated in maternal plasma during labour, suggesting chemokines contribute to peripheral inflammatory events during labour. Differences in chemokine expression patterns between TL and idiopathic PTL may be attributable to suppression of chemokine expression by betamethasone administered to women in PTL; this was supported by in vitro evidence of chemokine downregulation by clinically relevant concentrations of the steroid. The current study provides compelling evidence that chemokines regulate decidual leukocyte recruitment during labour. The 6 chemokines identified represent potential novel therapeutic targets to block PTL.

show abstract

The Chemokine Receptor CCR2 Is Not Required for Successful Initiation of Labor in Mice1

Cited by 14 publications

References 37 publications

Myometrial immune cells contribute to term parturition, preterm labour and post‐partum involution in mice

Myometrial immune cells contribute to term parturition, preterm labour and post‐partum involution in mice

Decidual Neutrophil Infiltration Is Not Required for Preterm Birth in a Mouse Model of Infection-Induced Preterm Labor

Identification of Chemokines Associated with the Recruitment of Decidual Leukocytes in Human Labour: Potential Novel Targets for Preterm Labour

Contact Info

Product

Resources

About