Research Topic

Danger signals triggering immune response and inflammation

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The immune system detects "danger", through a series of what we now call damage associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues. DAMPS also known as alarmins, are molecules released by stressed cells undergoing necrosis that ...

The immune system detects "danger", through a series of what we now call damage associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues. DAMPS also known as alarmins, are molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the immune and inflammatory response. DAMPs vary greatly depending on the type of cell (epithelial or mesenchymal) and injured tissue. Some endogenous danger signals are heat-shock proteins, HMGB1 (high-mobility group box 1), reactive oxygen intermediates, extracellular-matrix breakdown products such as hyaluronan fragments, neuromediators and cytokines like the interferons (IFNs). Non-protein DAMPs include ATP, uric acid, heparin sulfate and DNA. Increased serum levels of these DAMPs have been associated with many inflammatory diseases, including sepsis and multiple organ failure, atherosclerosis, age-associated insulin resistance, arthritis, lupus, Crohn’s disease, graft-versus-host disease, and cancer. Therapeutic strategies are being developed to modulate the expression of these DAMPs for the treatment of these diseases.

A vast number of reviews have already been published in this area, thus in an effort to not duplicate what has already been written, we will focus on recent discoveries particularly in disease models that are epidemic in Western Society: insulin resistance, cardiovascular diseases, allergies, autoimmune diseases, chronic inflammatory diseases, and cancers. Recent publications proposed a role for heat shock proteins and other DAMPs in tumor immunosurveillance, hematopoiesis and protection of the intestinal stem cell niche. IL-22 has also recently been shown to protect the intestinal stem cell niche during graft-versus-host disease. The HMGB-1 receptor (Siglec-G)/CD24 axis controls the severity of graft-versus-host disease. These interactions are influenced by the intestinal microbiome. ATP/ ectonucleotidases as well as IFN-alpha inducible signatures have also recently been involved in the development of acute and chronic graft-versus-host disease. Finally, soluble ST2 −a member of IL-1 receptor family− levels are increased in patients with active inflammatory bowel disease, cardiac diseases, insulin resistance and diabetes mellitus, acute cardiac allograft rejection, graft-versus-host disease, and myeloproliferative neoplasms in several patient cohorts. Furthermore, the ST2/IL-33 axis is routed in the pathogenesis of these diseases. A key role of ST2+ regulatory T cells has also been found in colitis, GVHD and insulin resistance. All these data highlight the role of DAMPs as major driver of disease mechanisms.

The goal of this research topic is to link DAMPs and chronic inflammatory diseases. Learning from these mechanisms of action, each researchers will propose novel targeted treatments. This collection of articles aims to promote interactions between researchers involved in understanding DAMPS/ alarmins and their regulation to limit their release and subsequent immunologically driven responses.


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