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Safeguarding of Fetal Growth by Mast Cells and Natural Killer Cells: Deficiency of One Is Counterbalanced by the Other

Meyer, Nicole, Woidacki, Katja, Maurer, Marcus, Zenclussen, Ana Claudia·2017·Frontiers in Immunology
DOI 10.3389/fimmu.2017.00711PMC PMC5472686
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Figure 1 Mast cell (MC)-deficient mice show increased numbers of uterine natural killer cells (uNKs) in contrast to wild type (WT). Bone marrow-derived MCs (BMMC) reconstitution restored this phenotype. Numbers of uNKs cells per 1 mm2 were quantified in Dolichos biflorus agglutinin lectin-stained 5 µm paraffin cross sections of implantations of WT C57BL/6J (n = 6), MC-deficient W-sh (n = 4), or BMMC-reconstituted W-sh (n = 4) mice (A) as well as in Cpa3+/+ control mice (n = 5) vs. MC-deficient Cpa3Cre/+ (n = 5) mice (B) at gd10. Results are presented as means with SEM. Also individual values are shown by dots, squares and triangles. Statistical differences were obtained using Mann–Whitney U-test (*P < 0.05). MCs, mast cells; NKs, natural killer cells; u, uterine; WT, wild type; BMMC, bone marrow-derived mast cells; W-sh, C57BL/6J-KitW-sh/W-sh.
Figure 1 Mast cell (MC)-deficient mice show increased numbers of uterine natural killer cells (uNKs) in contrast to wild type (WT). Bone marrow-derived MCs (BMMC) reconstitution restored this phenotype. Numbers of uNKs cells per 1 mm2 were quantified in Dolichos biflorus agglutinin lectin-stained 5 µm paraffin cross sections of implantations of WT C57BL/6J (n = 6), MC-deficient W-sh (n = 4), or BMMC-reconstituted W-sh (n = 4) mice (A) as well as in Cpa3+/+ control mice (n = 5) vs. MC-deficient Cpa3Cre/+ (n = 5) mice (B) at gd10. Results are presented as means with SEM. Also individual values are shown by dots, squares and triangles. Statistical differences were obtained using Mann–Whitney U-test (*P < 0.05). MCs, mast cells; NKs, natural killer cells; u, uterine; WT, wild type; BMMC, bone marrow-derived mast cells; W-sh, C57BL/6J-KitW-sh/W-sh.CC BY · PubMed Central
Figure 2 Interleukin (IL)-15-deficient mice are characterized by very low levels of peripheral (p) and the absence of uterine natural killer cells (uNKs) in contrast to wild-type mice. Percentages of CD122+CD3−NK1.1+ pNKs in spleen (A), blood (B), mesenteric lymph nodes (LN) (C), and inguinal LNs (D) at gd5 and gd10 were analyzed by flow cytometry in samples from C57BL/6N (n = 5–6) or IL-15−/− (n = 6) mice. Results are presented with squares showing the individual values for each mouse and medians are indicated. Statistical analysis was performed by the Mann–Whitney U-test (**P < 0.001). Representative Dolichos biflorus agglutinin (DBA) lectin-stained cross sections of implantations from C57BL/6N (E) or IL-15−/− (F) mice at gd10 are depicted (scale bar = 500 μm). uNKs can be identified as DBA lectin-positive, brown-stained cells within the decidua basalis (dashed lines marked area). Lower pictures show cutouts from the decidua basalis with higher magnification (scale bar = 100 μm) (F) confirms the absolute NK absence at gd10. IL, interleukin; p, peripheral; u, uterine; LN, lymph nodes; DBA, dolichos biflorus agglutinin.
Figure 2 Interleukin (IL)-15-deficient mice are characterized by very low levels of peripheral (p) and the absence of uterine natural killer cells (uNKs) in contrast to wild-type mice. Percentages of CD122+CD3−NK1.1+ pNKs in spleen (A), blood (B), mesenteric lymph nodes (LN) (C), and inguinal LNs (D) at gd5 and gd10 were analyzed by flow cytometry in samples from C57BL/6N (n = 5–6) or IL-15−/− (n = 6) mice. Results are presented with squares showing the individual values for each mouse and medians are indicated. Statistical analysis was performed by the Mann–Whitney U-test (**P < 0.001). Representative Dolichos biflorus agglutinin (DBA) lectin-stained cross sections of implantations from C57BL/6N (E) or IL-15−/− (F) mice at gd10 are depicted (scale bar = 500 μm). uNKs can be identified as DBA lectin-positive, brown-stained cells within the decidua basalis (dashed lines marked area). Lower pictures show cutouts from the decidua basalis with higher magnification (scale bar = 100 μm) (F) confirms the absolute NK absence at gd10. IL, interleukin; p, peripheral; u, uterine; LN, lymph nodes; DBA, dolichos biflorus agglutinin.CC BY · PubMed Central
Figure 3 Interleukin (IL)-15−/− mice showed impaired remodeling of spiral arteries (SAs), but no hypertension throughout pregnancy. While natural killer cell (NK) absence had no impact on fetal growth, it was associated with higher placental weight and lower fetoplacental-index (FPI). (A) SA wall and lumen perimeters of 3–10 SAs per animal of BL/6N (n = 6) and IL-15−/− (n = 5) mice were measured and SA wall-to-lumen ratio were calculated. Results are presented as means with SEM. Statistical differences were obtained using Mann–Whitney U-test (**P < 0.01). (B) Representative images of H/E-stained sections (scale bar = 50 μm) and immunofluorescence for smooth muscle (SM) actin and SM actin + DAPI (scale bar = 20 μm) of SAs (indicated by arrows) of BL/6N and IL-15−/− mice are shown. Systolic (C) and diastolic blood (D) pressure values for pregnant C57BL/6N (n = 5) or IL-15−/− (n = 5) mice from gd0 to gd18. Data were recorded every second day. For (C,D), results are presented as mean ± SEM. Statistical differences were obtained using Mann–Whitney U-test (*P < 0.05,). Fetal weights (E), placental weights (F), and FPI (G) from C57BL/6N (mothers: n = 5, fetus/placenta: n = 46) or IL-15−/− (mothers: n = 5, fetus/placenta: n = 29) females at gd18. For (E–G), results are presented with squares showing individual values for each fetus/placenta and means are indicated. Statistical differences were obtained using unpaired t-test (*P < 0.05, ***P < 0.001). IL, interleukin; SA, spiral arteries, NK, natural killer cells; FPI, fetoplacental-index; SM, smooth muscle.
Figure 3 Interleukin (IL)-15−/− mice showed impaired remodeling of spiral arteries (SAs), but no hypertension throughout pregnancy. While natural killer cell (NK) absence had no impact on fetal growth, it was associated with higher placental weight and lower fetoplacental-index (FPI). (A) SA wall and lumen perimeters of 3–10 SAs per animal of BL/6N (n = 6) and IL-15−/− (n = 5) mice were measured and SA wall-to-lumen ratio were calculated. Results are presented as means with SEM. Statistical differences were obtained using Mann–Whitney U-test (**P < 0.01). (B) Representative images of H/E-stained sections (scale bar = 50 μm) and immunofluorescence for smooth muscle (SM) actin and SM actin + DAPI (scale bar = 20 μm) of SAs (indicated by arrows) of BL/6N and IL-15−/− mice are shown. Systolic (C) and diastolic blood (D) pressure values for pregnant C57BL/6N (n = 5) or IL-15−/− (n = 5) mice from gd0 to gd18. Data were recorded every second day. For (C,D), results are presented as mean ± SEM. Statistical differences were obtained using Mann–Whitney U-test (*P < 0.05,). Fetal weights (E), placental weights (F), and FPI (G) from C57BL/6N (mothers: n = 5, fetus/placenta: n = 46) or IL-15−/− (mothers: n = 5, fetus/placenta: n = 29) females at gd18. For (E–G), results are presented with squares showing individual values for each fetus/placenta and means are indicated. Statistical differences were obtained using unpaired t-test (*P < 0.05, ***P < 0.001). IL, interleukin; SA, spiral arteries, NK, natural killer cells; FPI, fetoplacental-index; SM, smooth muscle.CC BY · PubMed Central
Figure 4 Interleukin (IL)-15−/− mice exhibit increased numbers of uterine mast cells (uMCs). (A) Numbers of uMCs per 1 mm2 were quantified in tolouidine blue-stained 5 µm paraffin sections from uteri of C57BL/6N (n = 6) and IL-15−/− mice (n = 6) at gd5. Results are presented as mean with SEM. Statistical differences were obtained using Mann–Whitney U-test (*P < 0.05). (B) Representative pictures for (A) are shown for C57BL/6N (i) and IL-15−/− (ii) mice (scale bar = 100 μm). uMCs (iii) are localized between the implantation sites and are indicated by arrows (scale bar = 20 μm) in (i) and (ii). (C) Percentages of CD117+FcεRα+ MCs in uterus (gd 5) or decidua (gd 10) samples were analyzed by flow cytometry. mRNA levels of MC-related proteases (Mcpt)-1 (D) and Mcpt-6 (E) in uterine (gd 5) and decidual (gd 10) tissue of BL/6N and IL-15−/− mice were measured. For (C–E), results are presented with squares showing individual values. Additionally, the medians are indicated. Statistical differences were obtained using non-parametric Mann–Whitney U-test (*P < 0.05, **P < 0.005). IL, interleukin; uMC, uterine mast cell; Mcpt, MC-related protease.
Figure 4 Interleukin (IL)-15−/− mice exhibit increased numbers of uterine mast cells (uMCs). (A) Numbers of uMCs per 1 mm2 were quantified in tolouidine blue-stained 5 µm paraffin sections from uteri of C57BL/6N (n = 6) and IL-15−/− mice (n = 6) at gd5. Results are presented as mean with SEM. Statistical differences were obtained using Mann–Whitney U-test (*P < 0.05). (B) Representative pictures for (A) are shown for C57BL/6N (i) and IL-15−/− (ii) mice (scale bar = 100 μm). uMCs (iii) are localized between the implantation sites and are indicated by arrows (scale bar = 20 μm) in (i) and (ii). (C) Percentages of CD117+FcεRα+ MCs in uterus (gd 5) or decidua (gd 10) samples were analyzed by flow cytometry. mRNA levels of MC-related proteases (Mcpt)-1 (D) and Mcpt-6 (E) in uterine (gd 5) and decidual (gd 10) tissue of BL/6N and IL-15−/− mice were measured. For (C–E), results are presented with squares showing individual values. Additionally, the medians are indicated. Statistical differences were obtained using non-parametric Mann–Whitney U-test (*P < 0.05, **P < 0.005). IL, interleukin; uMC, uterine mast cell; Mcpt, MC-related protease.CC BY · PubMed Central

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Research works printed but not linked: 31

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Authors
Meyer, N., Woidacki, K., Maurer, M., & Zenclussen, A. C.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2017-06-16
Volume
8
ISSN
1664-3224
DOI
10.3389/fimmu.2017.00711
PMC
PMC5472686
Cited by
29
References
1
Funders
Deutsche Forschungsgemeinschaft (ZE 526/6-2)

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