AIMS: Hofbauer cells (HBCs) are placental macrophages playing various roles during normal and complicated pregnancies, and of the latter, chorioamnionitis is the most frequent. METHODS: In placenta with chorioamnionitis, we examined immunohistochemical expression profiles of IL-1β, IL-10, and their potential regulators, CYP2C8 and soluble epoxide hydrolase (sEH), in Hofbauer cells and compared the results with our previously published data for normal placenta. RESULTS: We found that the expression profiles of the studied proteins in Hofbauer cells in chorioamnionitis differs from normal placenta. In chorioamnionitis, HBCs showed a moderate expression of IL-1β together with a weak expression of IL-10 and CYP2C8. Contrary to normal placenta, HBCs in chorioamnionitis express sEH. We demonstrated a moderate positive correlation between the expression of CYP2C8 and sEH in chorioamnionitis (Spearman r = 0.5654), suggesting enhanced degradation of anti-inflammatory epoxyeicosatrienoic acids. Moreover, the relations of IL-1β and IL-10 to CYP2C8, previously described in normal placenta, disappeared. Furthermore, a weak expression of anti-inflammatory IL-10 in chorioamnionitis was accompanied by change in circularity of HBCs (Spearman r = 0.8193). CONCLUSION: Taken together, these findings suggest a possible alteration of the anti-inflammatory role of HBCs and its regulation in chorioamnionitis.

Department of Histology and Embryology Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

See more in PubMed

Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci 2011;1221(1):80-7. DOI

Fu B, Wei H. Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface. Sci China Life Sci 2016;59(12):1224-31. PubMed DOI

Kim SY, Romero R, Tarca AL, Bhatti G, Kim CJ, Lee J, Elsey A, Than NG, Chaiworapongsa T, Hassan SS, Kang GH, Kim JS. Methylome of fetal and maternal monocytes and macrophages at the feto-maternal interface. Am J Reprod Immunol 2012;68(1):8-27. DOI

Bulmer JN, Johnson PM. Macrophage populations in the human placenta and amniochorion. Clin Exp Immunol 1984;57(2):393-403. PubMed

Böckle BC, Sölder E, Kind S, Romani N, Sepp NT. DC-sign+ CD163+ macrophages expressing hyaluronan receptor LYVE-1 are located within chorion villi of the placenta. Placenta 2008;29(2):187-92. PubMed DOI

Joerink M, Rindsjö E, van Riel B, Alm J, Papadogiannakis N. Placental macrophage (Hofbauer cell) polarization is independent of maternal allergen-sensitization and presence of chorioamnionitis. Placenta 2011;32(5):380-5. PubMed DOI

Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci 2008;13:453-61. DOI

Svensson J, Jenmalm MC, Matussek A, Geffers R, Berg G, Ernerudh J. Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-10. J Immunol 2011;187(7):3671-82. DOI

Swieboda D, Johnson EL, Beaver J, Haddad L, Enninga EAL, Hathcock M, Cordes S, Jean V, Lane I, Skountzou I, Chakraborty R. Baby's First Macrophage: Temporal Regulation of Hofbauer Cell Phenotype Influences Ligand-Mediated Innate Immune Responses across Gestation. J Immunol 2020; 204(9):2380-91. DOI

Tauber Z, Foltynkova T, Cizkova K. Morphometric analysis of Hofbauer cells in normal placenta and chorioamnionitis in humans. Anat Histol Embryol 2021;50(2):396-403. PubMed DOI

Yao Y, Xu XH, Jin L. Macrophage Polarization in Physiological and Pathological Pregnancy. Front Immunol 2019;10:792. PubMed DOI

Reyes L, Golos TG. Hofbauer Cells: Their Role in Healthy and Complicated Pregnancy. Front Immunol 2018;9:2628. PubMed DOI

Tauber Z, Chroma K, Baranova R, Cizkova K. The expression patterns of IL-1β and IL-10 and their relation to CYP epoxygenases in normal human placenta. Ann Anat 2021 [Epub ahead of print] doi: 10.1016/j.aanat.2020.151671 PubMed DOI

Seval Y, Korgun ET, Demir R. Hofbauer cells in early human placenta: possible implications in vasculogenesis and angiogenesis. Placenta 2007;28(8-9):841-5. PubMed DOI

Loegl J, Hiden U, Nussbaumer E, Schliefsteiner C, Cvitic S, Lang I, Wadsack C, Huppertz B, Desoye G. Hofbauer cells of M2a, M2b and M2c polarization may regulate feto-placental angiogenesis. Reproduction 2016;152(5):447-55. PubMed DOI

Ben Amara A, Gorvel L, Baulan K, Derain-Court J, Buffat C, Vérollet C, Textoris J, Ghigo E, Bretelle F, Maridonneau-Parini I, Mege JL. Placental macrophages are impaired in chorioamnionitis, an infectious pathology of the placenta. J Immunol 2013;191(11):5501-14. DOI

Schliefsteiner C, Peinhaupt M, Kopp S, Lögl J, Lang-Olip I, Hiden U, Heinemann A, Desoye G, Wadsack C. Human Placental Hofbauer Cells Maintain an Anti-inflammatory M2 Phenotype despite the Presence of Gestational Diabetes Mellitus. Front Immunol 2017;8:888. PubMed DOI

Sisino G, Bouckenooghe T, Aurientis S, Fontaine P, Storme L, Vambergue A. Diabetes during pregnancy influences Hofbauer cells, a subtype of placental macrophages, to acquire a pro-inflammatory phenotype. Biochim Biophys Acta 2013;1832(12):1959-68. PubMed DOI

Tamblyn JA, Lissauer DM, Powell R, Cox P, Kilby MD. The immunological basis of villitis of unknown etiology - review. Placenta 2013;34(10):846-55. PubMed DOI

Tang Z, Buhimschi IA, Buhimschi CS, Tadesse S, Norwitz E, Niven-Fairchild T, Huang ST, Guller S. Decreased levels of folate receptor-β and reduced numbers of fetal macrophages (Hofbauer cells) in placentas from pregnancies with severe pre-eclampsia. Am J Reprod Immunol 2013;70(2):104-15. DOI

Mueller-Heubach E, Rubinstein DN, Schwarz SS. Histologic chorioamnionitis and preterm delivery in different patient populations. Obstet Gynecol 1990;75(4):622-6. PubMed

Dammann O, Leviton A. Maternal Intrauterine Infection, Cytokines, and Brain Damage in the Preterm Newborn. Pediatr Res 1997;42(1):1-8. DOI

Gaudet LM, Smith GN. Cerebral palsy and chorioamnionitis: the inflammatory cytokine link. Obstet Gynecol Surv 2001;56(7):433-6. DOI

Ramsey PS, Lieman JM, Brumfield CG, Carlo W. Chorioamnionitis increases neonatal morbidity in pregnancies complicated by preterm premature rupture of membranes. Am J Obstet Gynecol 2005;192(4):1162-6. DOI

Spector AA, Fang X, Snyder GD, Weintraub NL. Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function. Prog Lipid Res 2004;43(1):55-90. DOI

Panigrahy D, Kalish BT, Huang S, Bielenberg DR, Le HD, Yang J, Edin ML, Lee CR, Benny O, Mudge DK, Butterfield CE, Mammoto A, Mammoto T, Inceoflu B, Jenkins RL, Simpson MA, Akino T, Lih FB, Tomer KB, Ingber DE, Hammock BD, Falck JR, Manthati VL, Kaipainen A, D´Amore PA, Puder M, Zeldin DC, Kieran MW. Epoxyeicosanoids promote organ and tissue regeneration. Roc Natl Acad Sci U S A 2013;110(33):13528-33. DOI

Thomson SJ, Askari A, Bishop-Bailey D. Anti-iflammatory effects of epoxyeicosatrienoic acids. Int J Vasc Med 2012;2012:605101. DOI

Bystrom J, Wray JA, Sugden MC, Holness MJ, Swales KE, Warner TD, Edin ML, Zeldin DC, Gilroy DW, Bishop-Bailey D. Endogenous epoxygenases are modulators of monocyte/macrophage activity. PLoS One 2011;6(10):e26591. PubMed DOI

Cizkova K, Tauber Z. Time-dependent expression pattern of cytochrome P450 epoxygenases and soluble epoxide hydrolase in normal human placenta. Acta Histochem 2018;120(6):513-9. PubMed DOI

Pineda-Torres M, Flores-Espinosa P, Espejel-Nunez A, Estrada-Gutierrez G, Flores-Pliego A, Maida-Claros R, Zaga-Clavellina V. Evidence of an immunosuppressive effect of progesterone upon in vitro secretion of proinflammatory and prodegradative factors in a model of choriodecidual infection. BJOG 2015;122(13):1798-807. PubMed DOI

Døllner H, Vatten L, Halgunset J, Rahimipoor S, Austgulen R. Histologic chorioamnionitis and umbilical serum levels of pro-inflammatory cytokines and cytokine inhibitors. BJOG 2002;109(5):534-9. PubMed DOI

Chatterjee P, Chiasson VL, Bounds KR, Mitchell BM. Regulation of the Anti-Inflammatory Cytokines Interleukin-4 and Interleukin-10 during Pregnancy. Front Immunol 2014;5:253. PubMed DOI

Puchner K, Iavazzo C, Gourgiotis D, Boutsikou M, Baka S, Hassiakos D, Kouskouni E, Economou E, Malamitsi-Puchner A, Creatsas G. Mid-trimester amniotic fluid interleukins (IL-1beta, IL-10 and IL-18) as possible predictors of preterm delivery. In vivo 2011;25(1):141-8. PubMed

Girard S, Tremblay L, Lepage M, Sébire G. IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol 2010;184(7):3997-4005. DOI

Hung TH, Chen SF, Hsu JJ, Hsieh CC, Hsueh S, Hsieh TT. Tumour necrosis factor-alpha converting enzyme in human gestational tissues from pregnancies complicated by chorioamnionitis. Placenta 2006;27(9-10):996-1006. PubMed DOI

Mitra R, Guo Z, Milani M, Mesaros C, Rodriguez M, Nguyen J, Luo X, Clarke D, Lamba J, Schuetz E, Donner DB, Puli N, Falck JR, Capdevila J, Gupta K, Blair IA, Potter DA. CYP3A4 mediates growth of estrogen receptor-positive breast cancer cells in part by inducing nuclear translocation of phospho-Stat3 through biosynthesis of (+/-)-14,15-epoxyeicosatrienoic acid (EET). J Biol Chem 2011;286(20):17543-59. DOI

Williams L, Bradley L, Smith A, Foxwell B. Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol 2004;172(1):567-76. DOI

Zeldin DC. Epoxygenase pathways of arachidonic acid metabolism. J Biol Chem 2001;276(39):36059-62. DOI

Eligini S, Crisci M, Bono E, Songia P, Tremoli E, Colombo GI, Colli S. Human monocyte-derived macrophages spontaneously differentiated in vitro show distinct phenotypes. J Cell Physiol 2013;228(7):1464-72. DOI

Schliefsteiner C, Ibesich S, Wadsack C. Placental Hofbauer Cell Polarization Resists Inflammatory Cues In Vitro. Int J Mol Sci 2020;21(3):736. DOI

Porcheray F, Viaud S, Rimaniol AC, Léone C, Samah B, Dereuddre-Bosquet N, Dormont D, Gras G. Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 2005;142(3):481-9. PubMed DOI

Vogel DY, Glim JE, Stavenuiter AW, Breur M, Heijnen P, Amor S, Dijkstra CD, Beelen RHJ. Human macrophage polarization in vitro: maturation and activation methods compared. Immunobiology 2014;219(9):695-703. PubMed DOI

Tedesco S, Bolego C, Toniolo A, Nassi A, Fadini GP, Locati M, Cignarella A. Phenotypic activation and pharmacological outcomes of spontaneously differentiated human monocyte-derived macrophages. Immunobiology 2015;220(5):545-54. PubMed DOI