Heparin fragments induce cervical inflammation by recruiting immune cells through Toll-like receptor 4 in nonpregnant mice
| Autor: | Hans Fischer, Anders Malmström, Manisha Yadav, Gunvor Ekman-Ordeberg, Jakob B Axelsson, Anna Åkerud, Jonas S. Erjefält |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Embryology Neutrophils Inflammation Cervix Uteri Biology 03 medical and health sciences 0302 clinical medicine Immune system Cell Movement Pregnancy Genetics medicine Animals Molecular Biology Cervix Mice Knockout Toll-like receptor Innate immune system Heparin Macrophages Obstetrics and Gynecology Interleukin Cell Biology Immunity Innate Mice Inbred C57BL Toll-Like Receptor 4 030104 developmental biology medicine.anatomical_structure Neutrophil Infiltration Reproductive Medicine 030220 oncology & carcinogenesis Myeloid Differentiation Factor 88 TLR4 Cancer research Female Interferon Regulatory Factor-3 medicine.symptom Cervical Ripening Signal Transduction Developmental Biology medicine.drug |
| Zdroj: | Molecular Human Reproduction. 27 |
| ISSN: | 1460-2407 1360-9947 |
| Popis: | Inflammation is a hallmark in the human cervix remodelling. A possible candidate inducing the inflammatory driven ripening of the cervix is the matrix component heparan sulphate, which has been shown to be elevated in late pregnancy in the cervix and uterus. Heparin and a glycol-split low molecular weight heparin (gsHep) with low anticoagulant potency has been shown to enhance myometrial contraction and interleukin (IL)-8 production by cervical fibroblasts. The aim of this study was to investigate the mechanism by which heparin promotes cervical inflammation. Wild-type, Toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88) and Interferon regulatory factor 3 (IRF3)-deficient mice were treated by deposition of gsHep into the vaginas of nonpregnant mice. To identify which cells that responded to the heparin fragments, a rhodamine fluorescent construct of gsHep was used, which initially did bind to the epithelial cells and were at later time points located in the sub-mucosa. The heparin fragments induced a strong local inflammatory response in wild-type mice shown by a rapid infiltration of neutrophils and to a lesser extent macrophages into the epithelium and the underlying extracellular matrix of the cervix. Further, a marked migration into the cervical and vaginal lumen was seen by both neutrophils and macrophages. The induced mucosal inflammation was strongly reduced in TLR4- and IRF3-deficient mice. In conclusion, our findings suggest that a TLR4/IRF3-mediated innate immune response in the cervical mucosa is induced by gsHep. This low anticoagulant heparin version, a novel TLR4 agonist, could contribute to human cervical ripening during the initiation of labour. |
| Databáze: | OpenAIRE |
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