Abstract
The neurotrophic factors are well known for their implication in the growth and the survival of the central, sensory, enteric and parasympathetic nervous systems. Due to these properties, neurturin (NRTN) and Glial cell-derived neurotrophic factor (GDNF), which belong to the GDNF family ligands (GFLs), have been assessed in clinical trials as a treatment for neurodegenerative diseases like Parkinson’s disease. In addition, studies in favor of a functional role for GFLs outside the nervous system are accumulating. Thus, GFLs are present in several peripheral tissues, including digestive, respiratory, hematopoietic and urogenital systems, heart, blood, muscles and skin. More precisely, recent data have highlighted that different types of immune and epithelial cells (macrophages, T cells, such as, for example, mucosal-associated invariant T (MAIT) cells, innate lymphoid cells (ILC) 3, dendritic cells, mast cells, monocytes, bronchial epithelial cells, keratinocytes) have the capacity to release GFLs and express their receptors, leading to the participation in the repair of epithelial barrier damage after inflammation. Some of these mechanisms pass on to ILCs to produce cytokines (such as IL-22) that can impact gut microbiota. In addition, there are indications that NRTN could be used in the treatment of inflammatory airway diseases and it prevents the development of hyperglycemia in the diabetic rat model. On the other hand, it is suspected that the dysregulation of GFLs produces oncogenic effects. This review proposes the discussion of the biological understanding and the potential new opportunities of the GFLs, in the perspective of developing new treatments within a broad range of human diseases.
Highlights
The glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs), comprisingGlial cell-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN), are proteins structurally related to transforming growth factor (TGF)-β and signal through the glycosyl-phosphatidylinositol (GPI)-anchored coreceptors (GFRα1–4), as a ligand binding component, and Ret receptor tyrosine kinase as a signaling component [1]
Another study described that following inflammation, gut microbial components like pathogen-associated molecular patterns are able to enhance the production of GDNF by the intestinal smooth muscle cells via TLR2 engagement [68]
Hyperglycemia is associated with enteric neuronal apoptosis, but this phenotype can be reverted by GDNF in diabetic mice via the activation of the PI3K/Akt signaling [76]
Summary
The glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs), comprising. GDNF, neurturin (NRTN), artemin (ARTN) and persephin (PSPN), are proteins structurally related to transforming growth factor (TGF)-β and signal through the glycosyl-phosphatidylinositol (GPI)-anchored coreceptors (GFRα1–4), as a ligand binding component, and Ret receptor tyrosine kinase as a signaling component [1]. GFLs are defined as molecules that maintain neuronal cells, they possess a range of functions outside the nervous system. MRNA expression patterns have been identified, most notably in epithelial-mesenchymal interactions, such as during skin, kidney, stomach, testis, lung, and tooth development. They play a critical role in the outgrowth of epithelial structures [11,12]. We will highlight the functions of GFLs and their emerging role in inflammation in different diseases, with the perspective of the development of new treatments
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