Inappropriate activation of invariant natural killer T cells and antigen‐presenting cells with the elevation of HMGB1 in preterm births without acute chorioamnionitis

Abstract

Problem Acute chorioamnionitis (aCAM) associated with microbial infection is a primary cause of preterm birth (PB). However, recent studies have demonstrated that innate immunity and sterile inflammation are causes of PB in the absence of aCAM. Therefore, we analyzed immune cells in the decidua of early to moderate PB without aCAM. Method of study Deciduas were obtained from patients with PB at a gestational age of 24+0 to 33+6 weeks without aCAM in pathological diagnosis. The patients were divided into two groups as follows: patients with labor and/or rupture of membrane (ROM) (no aCAM with labor and/or ROM: nCAM‐w‐LR), and patients without labor and/or ROM (no aCAM without labor and/or ROM: nCAM‐w/o‐LR). The immune cells and high mobility group box 1 (HMGB1) levels in the decidua were analyzed using flow cytometry. Co‐culture of CD56+ cells with dendritic cells (DCs) and macrophages obtained from the decidua was also performed in the presence of HMGB1. Results The nCAM‐w‐LR group demonstrated an accumulation of iNKT cells, and increased expression of HMGB1, TLR4, receptors for advanced glycation end products, and CD1d on DCs and macrophages. HMGB1 facilitated the proliferation of iNKT cells co‐cultured with DCs and macrophages, which was found to be inhibited by heparin. Conclusions Inappropriate activation of innate immune cells and increased HMGB1 expression may represent parturition signs in human pregnancy. Therefore, control of these cells and HMGB1 antigenicity may be represent a potential therapeutic target for the prevention of PB.

Downregulation of pattern recognition receptors on macrophages involved in aggravation of endometriosis

“…[15][16][17] In reproduction, sterile inflammation, alarmins, and their receptors are thought to be involved in various complications, such as infertility, preterm birth, miscarriage, fetal growth restriction, preeclampsia, and endometriosis. 5,[18][19][20] Previous our study found that the cytoplasmic HMGB1 level increased in antigen-presenting cells (APCs) obtained from EOC and that the activation of the acquired immune system was established more efficiently than the innate immune system. 21 Based on our study and recent reports, it is possible that the sterile inflammation induced by alarmins and their receptors might be involved in the onset or development of endometriosis.…”

HMGB1: a double-edged sword and therapeutic target in the female reproductive system

“…Once activated, these iNKT cells act by secrete a range of cytokines and lysis granules, such as IFN-γ, perforin and granzyme B, which may cause damage to both fetal and maternal tissues. As a result, the release of HMGB1 is more enhanced, leading to further inflammation and the promotion of PTB development ( 153 ). In addition, one study found that the mRNA expression and protein levels of several molecules, including HMGB1, RAGE, NF-κB/p65, matrix metalloproteinase (MMP)-9, and MMP-2, were significantly increased in the HMGB1-RAGE pathway in pregnant women who had experienced pPROM compared with those who had experienced normal full-term pregnancies.…”

“…Low molecular weight heparin (LMWH) is a commonly used anticoagulant for treating pregnancy complications such as recurrent miscarriage, pre-eclampsia, and fetal growth restriction ( 153 , 178 ). Although there is no evidence for the beneficial effects of heparin in reducing adverse neonatal outcomes ( 179 ).…”

The Role of Type I and Type II NKT Cells in Materno-Fetal Immunity

“…Preterm birth is commonly defined as any birth before 37 weeks completed weeks of gestation [ 80 ]. In the case of preterm birth without chorioamnionitis, there could be an enhanced accumulation and aberrant activation of decidual iNKT cells as the initial event of the pregnancy complication as suggested by one group [ 81 , 82 ] while others could not confirm it [ 60 ].…”