Innate Immunity at mucosal sites

The mucosae represent the border between our body and the environment, and they act as the first barrier against infections. Therefore, inflammatory responses must be tightly regulated to combat infection without causing excessive self-damage or interfering with the repair process. An imbalance in these processes could result in the loss of barrier function and tissue functionality.

Achille Broggi and his team study the interplay between the immune system and the mucosal layer, with a particular interest in understanding how immune mediators production and functions are regulated in the intestinal mucosa and how they regulate the pathogenesis of inflammatory bowel disease (IBD)

The mucosae represent our interface with the environment and the first line of defense against invading pathogens. Their function as physical barriers means that the inflammatory process at these sites must be tightly regulated to combat invading pathogens while limiting collateral damage to self-tissues. In a healthy individual, this balance allows for efficient repair and barrier reestablishment once the infection is resolved.

We found that a class of antiviral cytokines called Interferon Lambda (IFN-λ) has an important role in this context.

Indeed, while IFN-λ is mainly sensed by mucosal epithelia and can thus directly protect them from pathogenic viral infections, we also found that it has a specific regulatory activity on inflammatory cells (neutrophils).

                                       A                                                            B

image 48        image 47

The intestinal crypt after radiation damage.
Histology slides depicting the mouse small intestinal mucosa of A) healthy mice, B) mice with epithelial damage following irradiation. After damage, intestinal epithelial cells proliferate and reconstitute tissue functionality. We are interested in the role of IFN-λ in this context.

This dual action of IFN-λ ensures the efficient control of viral pathogens and, at the same time, controls potential detrimental inflammatory reactions.

We have recently found, however that there is a dark side of IFN-λ. Indeed when IFN-λ is aberrantly expressed at the tail end of a viral infection, can impair the ability of epithelial cells to proliferate and repair damaged tissues., In these pathological conditions, IFN-λ can inhibit  repair and the resolution of inflammation, which are needed to return to health.

This ability of IFN-λ to both protect the mucosae and, in pathological settings, to have the ability to be detrimental during repair, makes it an extremely interesting cytokine to study in the context of mucosal diseases.

In this context we are interested in studying the role of IFN-λ in intestinal inflammation, and how naturally occurring IFN-λ, produced in response to the intestinal flora, can impact the pathogenesis of autoimmune diseases of the gut such as IBD.

We will explore this question by using several different models, ranging from in vivo mouse models of IBD to in vitro models of epithelial biology such as human and mouse intestinal organoids and model of mouse and human immune cells.

Understanding how IFN-λ differently regulates the immune and epithelial response will be extremely useful to devise therapies able to intervene on the one hand to favor the anti-inflammatory role of IFN-λ, and on the other hand to interfere with its detrimental role during tissue recovery.