Th17 Immunity and the Inflammation of Aging in Intestinal Barrier Dysfunction

The immune system is a very complex network of many different cell types, signals, and layered responses. It is much more subdivided and varied than the broad distinction between innate and adaptive immune components might lead one to believe. As a whole the immune system runs awry in later life, becoming both overly active and incompetent at the same time. Chronic inflammation and an inability to adequately defend against pathogens is the result. Many researchers are engaged in picking apart the details of this failure state, and the work here is a representative example of this sort of work, with a narrow focus on one smaller portion of the immune system and its responsibilities.

Chronic sub-clinical inflammation of aging, resulting from lifetime exposures to pathogens in concert with impaired immune responses, poses an obstinate challenge to the health span of the growing elderly population. Several factors contribute to the increased morbidity/mortality of older adults, including loss of naïve lymphocytes, exhaustion of adaptive immunity, and a skew toward proinflammatory responses. Additionally, loss of intestinal homeostasis and perturbations in epithelial barrier protective immune functions have recently emerged as key factors underlying chronic inflammation and age-related comorbidities.

Defense of epithelial barriers against invading pathogens and maintenance of mucosal homeostasis mainly relies on the Th17-type immunity, also known as type-17 and Th3 immunity, which is characterized by IL-17/IL-22 cytokine production. IL-17 predominantly triggers the influx of neutrophils and tissue repair, while IL-22 stimulates proliferation of epithelial cells, and regulates epithelial permeability, production of mucus, antimicrobial proteins, and complement to help maintain barrier integrity.

Our laboratory has shown that systemic inflammation in older macaques was associated with reduced Th17-type cytokine functions of CD161+ immune cells. This correlated with circulating biomarkers of leaky gut and microbial translocation, suggesting a link between intestinal barrier dysfunction and inflammaging. There is significant evidence showing that Th17-type immunity and epithelial barrier functions have an important role in the immune response and inflammation of aging; however, the precise cellular and molecular mechanisms underlying altered Th17-type responses in aging humans remain to be elucidated.

The health and diversity of our microbiome and how it influences Th17-type responses should also be of value for mucosal immunity in the context of aging. A clear understanding of epithelial barrier protective Th17-type responses will aid the development of targeted therapies, specifically tailored for the elderly.



New antibody therapy may reverse diabetic retinopathy and other eye conditions

heir new publication describes how one of the antibodies, specifically activating the Frizzled4-LRP5 receptor complex, successfully stimulated Wnt signaling in the blood-retina barrier and effectively restored barrier function.

The antibody attaches to two key cell surface receptors (Frizzled4 and LRP5) bringing them close together, and this induced proximity activates the Wnt pathway that maintains the blood vessels.

The team first tested the antibody in cell cultures and found that it was a highly precise way to trigger the signaling pathway and restore barrier function. They then tested the antibody in different mouse models in collaboration with Harald Junge at the University of Minnesota and AntlerA Therapeutics, a start-up company founded by Angers and Sidhu. One model represented a genetic eye condition and one represented diabetic retinopathy.

Remarkably, the antibody restored the barrier function and corrected retinal blood vessel formation in these mice. In addition, it normalized the pathological formation of new blood vessels, one of the consequences of a leaky blood-retina barrier that causes further eye damage.

With the antibody's promising preclinical results, AntlerA Therapeutics will now lead the commercialization and translation to clinical studies.

While the current study's results are focused on eye conditions, the similarities between the blood-retina barrier and blood-brain barrier mean that its applications could be much broader than eye conditions.

"The retinal vasculature was the first indication, and we have new funding to explore the role of this pathway in other contexts," said Angers. "For example, we are testing whether this antibody could have implications in the blood-brain barrier and whether it could repair the barrier in the context of stroke."

"We've found a way to activate Wnt signaling very precisely in order to have a viable therapeutic opportunity and actually treat these diseases," added Chidiac. "We anticipate that this could have enormous impact in diverse applications in regenerative medicine."

Sounds like it could also work on Alzheimers.

Posted by: Robert Read at June 10th, 2021 11:05 AM
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