Tissue inflammation and immunity

Perceive and respond to stress

The cellular response to stress (infection, radiation, poisoning) is a very ancient theme of biological interest. To deliberately cause an imbalance in a tissue is the simplest experimental means to study the mechanisms for the return to normal of the latter. One of the central functions of the immune system is to maintain tissue integrity, so there are mechanisms that allow a tissue to trigger a protective or restorative immune response to stress.

Inside the cell, stress induces a number of biochemical disturbances including oxidative stress*, resulting in the overproduction of very aggressive chemical compounds. They can attack the cell components and contribute to various pathologies (inflammation, cardiovascular diseases, cancers). The team of Philippe Naquet attempts to characterize the function of novel molecules involved in tissues responding to stress.

"Our goal is to study how stress is detected in a tissue and how stress modulates the "decisions" of tissues, e.g. switching on the recruitment of immune cells," said Philippe Naquet. "If stress detection fails, then its management is no longer optimal and disease may occur."

Further exploring the link between stress and immunology, Philippe Naquet's team has identified one of the major factors involved in the detection of stress and its consequences. The thymus is an organ important for the production and function of white blood cells, By studying cellular and functional reconstitution of the thymus in irradiated mice, they found a family of molecules whose function was then completely unknown, a rare event biological research.

Philippe Naquet, reflecting on the history of the discovery of molecules of the Vanin family: "In an immunological context (the reconstitution of the thymus) our discovery was unexpected. Vanin-1 had never been incorporated in any field of biology and nobody knew what it was used for. It took almost 7 years to associate a function with this molecule and this has been possible only by developing a mouse lacking the gene encoding it. And even then! Mice without vanin-1 are apparently normal, except that when they are subjected to stress, we can observe the impact of our genetic modification."

[[wysiwyg_imageupload::]]Distribution of mouse vanin-1 at the level of Peyer’s patch of the small intestine: vanin-1 (green), M cells (red), actin filaments (blue).
Copyright Philippe Naquet, CIML.

It is on the physiology of the bowel wall that effects were most pronounced. Vanin-1 is strongly expressed in this tissue, which is particularly vulnerable to infectious and inflammatory stress because of the presence of a large number of bacteria in constant contact with its surface.

The unstable equilibrium of the stress response

"We spent several years studying vanin-1 deficient mice in different acute digestive stress situations (drug-induced ulcers, colitis caused by bacterial infections...). In these first models the absence of Vanini-1 enhanced the condition of the mice. Mice lacking Vanin-1 are generally more resistant to oxidative stress, therefore they are less sick than the normal mice," says Philippe Naquet. "vanin-1 acts as a sensor of oxidative stress, but in these situations it triggers reactions that are too intense and aggravate the attack on the tissue. However, we also found experimental systems in which vanin-1 plays a protective role against stress, since its absence is deleterious. Vanin-1 plays a central role but it is also finely regulated in stress management: its mechanism of action is highly dependent on context."
This also explains why the study of the function of this family of molecules could not be conducted in simple cell models in vitro but required the development of "full" model in mice where multiple potential targets of vanin are present.

The questions posed by Philippe Naquet's team today also focus in part on the partners of vanin-1 and identification of cellular targets that react when it emits the detection signal of stress.

In addition, Philippe Naquet and his team are trying to demonstrate the applicability of their research to human pathophysiology: "What is the equivalent of this system in humans?" asks Philippe Naquet. "If there is an equivalent, this control system must play a major role. We now have tools to detect molecules equivalent to vanin-1 in samples from patients, which should guide us towards diseases where it plays a role in oxidative stress responses."
Since this molecule is on the surface of cells of certain tissues, it is an easily accessible target for drugs. Vanin-1 is a key element in the perception of stress and induction of a response to this stress, so its human counterpart might be a good therapeutic target for many diseases induced by oxidative stress.

* Attack of the components of the cell by free radicals, highly aggressive chemical molecules constantly produced by normal cell metabolism.