“This was a completely unexpected finding. We had suspected that decidual tissue had a role to play in maintaining the immune balance between the mother and the fetus, but we had never thought of this pathway.”

—SK Dey, PhD

Scientists have known for years that inflammatory reactions during pregnancy to infections and other causes can trigger preterm birth. Now experts at Cincinnati Children’s report that the systemic inflammatory process begins in an unexpected location that suggests new ways to develop preventative medications.

As pregnancy progresses, a mucosal lining called the decidua envelopes the developing fetus and lines the mother’s uterus. By studying multiple kinds of mouse models, researchers have learned that one major risk factor for preterm birth begins in the endothelial cells that line the interior of blood vessels within the decidua.

The study, published online May 7, 2019, in the journal Cell Reports, was led by first authors Wenbo Deng, PhD, and Jia Yuan, PhD, and senior author Sudhansu K. Dey, PhD, Director of the Division of Reproductive Sciences at Cincinnati Children’s.

“This was a completely unexpected finding,” Dey says. “We had suspected that decidual tissue had a role to play in maintaining the immune balance between the mother and the fetus, but we had never thought of this pathway.”

How a delicate balance gets disrupted

Successful pregnancy depends in part upon a mother’s immune system being strong enough to fight off infections that could threaten the growing fetus without being so strong that her body attacks the fetus as if it were an infection.

The new study was based on analyzing how mouse dams react at the molecular level when they were given LPS, a drug that mimics how infections can trigger inflammation and preterm birth. The research team learned that the reaction to LPS begins with TLR4 activation present on endothelial cells within the decidual blood vessels.

TLR4 activation by LPS prompts the release of inflammatory cytokines including interleukin 6 (IL6), one element of the body’s defense system against infection. Normally, when IL6 rises, another interleukin, IL10, responds to knock the inflammation back down. However, if TLR4 activation is excessive it overwhelms the IL10 response, tipping the immune balance toward dangerous levels of inflammation and increasing the risk of preterm birth.

The research team examined how the mouse inflammation system maintains this balance. Deleting the gene Tlr4 in the decidual tissue made mice highly sensitive to LPS, even at low doses, and highly likely to experience preterm birth. Administering IL10 helped these mice avoid preterm birth.

However, deleting Tlr4 in the endothelial cells of the blood vessels made mice highly resistant to LPS-triggered preterm birth, even at high doses.

Zeroing in on a potential treatment target

“These findings highlight a previously unappreciated role of endothelial TLR4 in inflammation-induced preterm birth and may offer a potential therapeutic target to prevent preterm birth,” the co-authors wrote.

Other research has already established that the TLR4 protein plays an important role in human delivery. Humans also have a similar pattern of IL10 expression and regulation.

The new study advances the concept that the decidua is crucial to fighting off infections and inflammation that threaten pregnancy but can do so only to a certain extent. Understanding how endothelial cells drive this inflammatory process suggests a new approach to preventing it or slowing it down.

“The demonstration of the critical role for TLR4 in the decidua through these elegant preclinical studies provides exciting new potential for intervention in preterm birth in humans, an area where new therapies are desperately needed,” says Louis Muglia, MD, PhD, Co-Director of Perinatal Institute and Director of the Center for Prevention of Preterm Birth at Cincinnati Children’s.

Next steps include further experiments to validate a potential treatment before human clinical trials can be launched.

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—By Tim Bonfield