Regenerative power of IL-22 in endometrial healing


The tissue that borders the uterus is known as the endometrium. This mucous membrane gets thicker before a potential pregnancy. The lining remains in place if a fertilized egg is implanted. If not, a menstrual cycle causes the endometrium to shrink and shed. Tight and adherens junctions modify cell-cell contacts along with the endometrium’s exceptional flexibility to accommodate the needs of the uterine layers that are undergoing change. Tetraspan transmembrane proteins called claudins are found in tight junctions. They assess the barrier qualities of this cell-cell contact, which occurs when the plasma membranes of two nearby cells come into touch, as in endothelia or epithelia. Endometrial integrity is greatly influenced by the direct cell-cell interactions that are made possible by tight and adherens junctions. Any modifications to these connections may affect endometrial permeability of the uterus and the renewal of uterine mucosal lining. A cytokine known as interleukin 22 (IL-22) is well known for its function in epithelial regeneration. IL-22 is a key signaling molecule that plays a significant role in number of essential physiological processes ranging from innate immune responses to tissue regeneration. Moreover, it is essential for regulating the inflammatory response in mucosal tissues.

In a new study published in the peer-reviewed Journal Frontiers in Immunology, Rosalind Franklin University of Medicine and Science researchers Dr. Umida Ganieva, Ms. Sylvia Schneiderman, Dr. Pengli Bu, Professor Kenneth Beaman and Professor Svetlana Dambaeva proposed that IL-22 plays a key role in the regeneration of uterine mucosal tissue following abortion brought on by inflammation. They discovered that IL-22 helps to heal the endometrium after LPS (lipopolysaccharide) treatment by working closely with the cell surface pathogen protector mucin-1, tight and adherens junctions, and indicators of the mesenchymal-epithelial transition.

The research team demonstrated that IL-22 upregulates cell surface pathogen protectors and strengthens tight junctions (mucin-1) (claudin-2 and claudin-10). They found that IL-22 controls epithelial-mesenchymal and mesenchymal-epithelial transition markers, which helps to remodel uterine tissue in an inflammatory environment. The lack of IL-22 in IL-22-/- mice was expected to impair endometrial regeneration following LPS-induced abortion and impair the mice’s capacity to conceive in future mating. Despite getting pregnant successfully in the first time, the IL-22-/- mice have considerably reduced fertility rates in subsequent matings following an abortion caused by LPS on gd 8.5. This might explain why IL-22-deficient animals can sustain the first pregnancy but cannot sustain subsequent pregnancies, since the lack of IL-22 might prevent stromal cells from transforming into epithelial tissue in a subsequent pregnancy.

According to the authors: IL-22 is crucial in regulating the overproduction of ECM during the postabortive uterine regeneration phase. Collagen-3 production was higher in IL-22-/- mice compared to the control group. Due to the lack of a significant difference between the groups, the regulation of proteolytic enzymes in endometrial healing following LPS-induced abortion is independent of IL-22.

The authors also noticed that the lack of IL-22 led to aberrant re-epithelization of the endometrium following the LPS challenge. In contrast to WT mice, the IL-22-/- mice had higher levels of E-cadherin and significantly lower levels of N-cadherin, but these differences may indicate a lack of proper complex formation between cadherins and WNT molecules because the IL-22-/- mice also had significantly lower expression levels of WNT-4 and WNT-7. Their findings show that the uterus in WT mice is already in an epithelial-mesenchymal status and ready for future pregnancies. In contrast the endometrium in IL-22-/- mice may be going through an intermediate step between the mesenchymal-epithelial and epithelial-mesenchymal transition.

In conclusion, in well- designed cellular and molecular experimental studies, Professor Svetlana Dambaeva and her colleagues showed that by controlling tight and adherens junctions, coordinating ECM proteins, and acting as an antibacterial barrier, IL-22 plays a vital role in the prevention of secondary infertility with inflammation and in post-inflammatory regeneration. Rosalind Franklin University scientists proposed that IL-22 may be a drug candidate used to treat secondary infertility and poor uterine regeneration brought on by infection and inflammation that take place during the initial pregnancy.

Regenerative power of IL-22 in endometrial healing - Medicine Innovates

About the author

Dr. Svetlana Dambaeva, MD, PhD, serves as a Director of Clinical Immunology Laboratory and as a Research Assistant Professor in the Center for Cancer Cell Biology, Immunology, and Infection at Chicago Medical School, Rosalind Franklin University of Medicine and Science. Dr. Dambaeva received her M.D. from the Siberian State Medical University and her Ph.D. in immunology from the Institute of Immunology, Moscow, Russia. She is certified as a Diplomate of the American Board of Medical Laboratory Immunology (ABMLI). She did her postdoctoral training at the Wisconsin National Primate Research Center, Department of Obstetrics and Gynecology, University of Wisconsin, Madison. She studied placental non-classical MHC class I molecules and unique endometrial leukocyte populations in various non-human primates and established herself as a key researcher in the reproductive immunology field. Dr. Dambaeva’s research interests include immune responses at the maternal-fetal interface and analysis of immune mechanisms of infertility and recurrent pregnancy loss. She has 89 publications with nearly 1000 citations in peer-reviewed journals and books. With a strong expertise in the clinical laboratory diagnostics and in the field of reproductive immunology, her goals are to develop and validate novel diagnostic tests that will help physicians to identify factors involved in the pathogenesis of infertility or recurrent pregnancy loss.

About the author

Umida Ganieva, MD, PhD, is a Postdoctoral Research Associate at the Clinical Immunology Laboratory, Center for Cancer Cell Biology, Immunology, and Infection at Chicago Medical School, Rosalind Franklin University of Medicine and Science. Umida received her MD from Andizhan State Medical Institute (Uzbekistan) and her MSc (Healthcare Administration) and PhD (Obstetrics, Gynecology and Gynecologic Oncology) in Nagoya University Graduate School of Medicine (Japan). Infertility issues like recurrent pregnancy loss and recurrent implantation failure have always been of high interest for Umida which she continues to study in her postdoctoral work. She believes that being a research oriented doctor offers the most complete and constant union of novelty, utility and efficacy.


Ganieva U, Schneiderman S, Bu P, Beaman K, Dambaeva S. IL-22 regulates endometrial regeneration by enhancing tight junctions and orchestrating extracellular matrix. Frontiers in Immunology. 2022 ;13:955576.

Go To Frontiers in Immunology.