Death Receptors, Non-Apoptotic Signaling Pathways and Inflammation

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Background

Death receptors, including tumor necrosis factor receptor 1 (TNFR1), Fas and the TRAIL receptors, DR4 and DR5, belong to the TNF receptor family. Their common characteristic is the presence of a death domain in their cytosolic fraction through which they can trigger cell death. While TNFR1 has been mainly studied for its function in inducing an inflammatory reaction and is involved in the etiology of many chronic inflammatory disorders, Fas and DR4/DR5 are best recognized for their ability to drive cell death signaling. Thus far, there are few studies investigating the physiological and pathophysiological consequences of non-apoptotic signaling pathways emanating from these death receptors.

Members of the TNF superfamily including BAFF, APRIL, CD95L, TRAIL, CD40L, OX40L and TNFα are involved in immune cell homeostasis (such as in T and B cells) and their deregulation has been implicated in the pathogenesis of several autoimmune and chronic inflammatory disorders including Systemic Lupus Erythematosus, Rheumatoid Arthritis (RA), Crohn’s disease and Multiple Sclerosis..

All of these ligands can trigger both anti- and pro-inflammatory responses depending on: (i) the stage of the disorder; (ii) the cell type in question and (iii) whether the ligand is membrane-bound or soluble. Furthermore, recent research suggests that TNF ligands, including CD40, OX40L, as well as TRAIL and FasL, may also be involved in the reshaping of the immune landscape in cancer, contributing to tumor progression and metastasis. However, the underlying mechanisms that are involved in these processes remain poorly understood.

To date, several therapeutics targeting the TNF family members have reached the clinic, with the most promising being anti-TNF drugs. These therapeutic agents which include infliximab (Remicade), adalimumab (Humira) and Etanercept (Enbrel), have been widely and successfully employed for the management of several inflammatory and autoimmune disorders such as RA, Ankylosing Spondylitis and Psoriasis. In addition, several monoclonal antibodies targeting TNF family members have been shown to modulate the functions of immune cells such as dendritic cells, macrophages and T cells, within the tumor microenvironment, boosting cytokine production and immunogenic anti-tumor responses.

However, side effects associated with anti-TNF therapeutics are common due to the role of the TNF superfamily in various biological processes. One of the most deleterious effects of anti-TNF treatments is increased risk to serious infection. This correlates with the major role played by TNF/TNFR pair in controlling pathogen spread, directly through its apoptotic function and/or indirectly by mounting an inflammatory response. Furthermore, immune modulation by these therapeutic agents can also cause prolonged alterations to immune cells, such as T cells, which can subsequently lead to the deregulation of the immune system and disease.

Taken together, although our understanding of the role of the TNF superfamily in inflammation, inflammatory disorders and cancer has increased in recent years, many challenges remain towards developing effective anti-TNF therapies to treat these conditions. Therefore, in this Research Topic, we aim to gather a collection of Original Research, Review and Opinion articles that cover the following topics:

1. The role of TNF/TNFR members in shaping immune responses that fuel chronic inflammation and consequently lead to pathophysiological changes.
2. Mechanisms of action of drugs targeting TNF/TNFR members in immune cells for the treatment of chronic inflammatory conditions, autoimmune diseases and cancer.
3. The role of the TNF superfamily in the modulation of immune cells in the tumor microenvironment.
4. Association of TNF/TNFR members with clinical outcome in patients with chronic inflammatory conditions and/or cancer.

Keywords: TNF, TNFR1, Fas, DR4/5, Death Receptors

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