Increase in complement iC3b is associated with anti-inflammatory cytokine expression during late pregnancy in mice.

Keigo Nakamura,Sayuri Fukushima,Kazuya Kusama,Kazuhiko Imakawa,Yoshihito Suda,Rulan Bai,Sadamasa Ishikawa,Mark D Zabel

doi:10.1371/journal.pone.0178442

Keigo Nakamura, Sayuri Fukushima + Show 6 more

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https://doi.org/10.1371/journal.pone.0178442

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Journal: PloS one	Publication Date: May 25, 2017
Citations: 9	License type: CC BY 4.0

Affiliation: Miyagi University, The University of Tokyo

Abstract

Immunological tolerance between fetal allograft and mother is crucial for pregnancy establishment and maintenance; however, these mechanisms particularly those during the latter part of pregnancy have not been definitively elucidated. The aim of this study was to examine the presence and potential function of innate immunity characteristic to the middle to late pregnancy. We first characterized up-regulated proteins in decidua from day 11 pregnant (P11) mice using 2D-PAGE, followed by MALDI-TOF/MS analysis. These analyses identified increased complement component 3 (C3) and its derivatives in P11 decidua. We then found that in the decidual tissues, C3 mRNA increased on P15 and remained high on P19. C3 is converted to C3b and then iC3b by complement component factor I (Cfi) and complement receptor 1-like protein (Crry), both of which were present in P19 placentas. In addition, iC3b proteins and its receptor CR3 (Cd11b/Cd18) in decidual and placental tissues increased toward the latter phase of pregnancy. Moreover, CR3 subunit CD11b protein was predominantly localized to spongiotrophoblast layer in the P19 placenta. Because iC3b is known to induce anti-inflammatory cytokine production, the analysis was extended to examine changes in pro- and anti-inflammatory cytokines, Il12, Il10, and Tgfb1. Il12 expression decreased in P15 and P19 placenta, while high mRNA expression of Il10 and Tgfb1 was found in P19 placental tissues. Furthermore, placental Il10 and Tgfb1 mRNAs were down-regulated when pregnant mice were treated with an anti-C3 antibody, detecting C3, C3b and iC3b. These results indicated that C3 derivatives, in particular, iC3b and its receptor CR3 were up-regulated at the fetal-maternal interface, and suggest that iC3b may regulate the placental expression of anti-inflammatory cytokines, IL10 and TGFB1, during the latter phase of pregnancy.

Highlights

Successful placentation and subsequent maintenance of pregnancy requires an intimate immunological relationship between mother and fetus [1]; these processes face a challenge because the fetus and placenta carry paternal genes allogenic to the maternal immune system
C3b is cleaved by complement component factor I (CFI) to generate inactive C3b and this process is mediated by complement receptor-1 (CR1, CD35), membrane cofactor protein (MCP), complement component factor H (CFH) and complement receptor 1-like protein (CRRY) [13, 14]
Increase in decidual and placental component 3 (C3), C3b, and inactive C3b (iC3b) toward the latter part of pregnancy in mice indicate that complement systems from middle to late pregnancy are likely functioning. iC3b is known as an opsonin for the innate immune system and binds the complement receptor, complement receptor type 3 (CR3), composed of CD11b and CD18, on the surface of granulocytes, monocytes, NK cells, T and B lymphocytes, causing the enhancement of phagocytosis [26, 27]

Summary

Introduction

Successful placentation and subsequent maintenance of pregnancy requires an intimate immunological relationship between mother and fetus [1]; these processes face a challenge because the fetus and placenta carry paternal genes allogenic to the maternal immune system. The semi-allogeneic fetus and the mother must establish complex immune systems in pregnancy, by which the fetal allograft is protected while invaders such as bacteria and other microorganisms are eliminated With this immunological paradox in mind, various studies on both innate and adaptive immune systems have been conducted over the last five decades [2,3,4,5,6,7,8]. In the anterior chamber of the eye, iC3b binding to complement receptor type 3 (CR3) is essential for anti-inflammatory cytokine production, resulting in the induction of tolerance [15] These findings indicate that in addition to known functions such as opsonization and anaphylatoxins classically characterized, complement systems have multiple functions, including the regulation of cytokine productions

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