Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi...Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.展开更多
Gastrointestinal diseases, specifically Crohn's disease, ulcerative colitis, diverticular disease, and primary biliary cirrhosis are all characterized by complicated inflammation of the digestive tract. Their path...Gastrointestinal diseases, specifically Crohn's disease, ulcerative colitis, diverticular disease, and primary biliary cirrhosis are all characterized by complicated inflammation of the digestive tract. Their pathology is multifactorial, and risk factors encompass both genetic and environmental factors. Recent advances in the genetic component of inflammatory bowel diseases(IBDs) have revealed that the tumor necrosis factor superfamily member 15(TNFSF15) contains a number of risk alleles associated not only with IBD but also with other diseases such as diverticular disease and primary biliary cirrhosis. These risk alleles in TNFSF15 and the altered expression of its gene product can serve as the common ground between these disorders by explaining at least some of the underlying processes that lead to a dysregulated immune response and subsequent chronic inflammation. Here, we aim to outline how the TNFSF15 gene is involved in the proliferation and cell fate of different populations of T cells and subsequently in the control of both pro-and anti-inflammatory cytokines. Furthermore, we summarize what is currently known of TNFSF15 control region variants, how they are associated with each mentioned disease, and how these variants can explain the autoimmune pathology of said diseases through altered TNFSF15 expression.展开更多
基金a Ph D fellowship by FCT-Fundacao para a Ciência Tecnologia (SFRH/BD/135868/2018)(to SSC)。
文摘Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
文摘Gastrointestinal diseases, specifically Crohn's disease, ulcerative colitis, diverticular disease, and primary biliary cirrhosis are all characterized by complicated inflammation of the digestive tract. Their pathology is multifactorial, and risk factors encompass both genetic and environmental factors. Recent advances in the genetic component of inflammatory bowel diseases(IBDs) have revealed that the tumor necrosis factor superfamily member 15(TNFSF15) contains a number of risk alleles associated not only with IBD but also with other diseases such as diverticular disease and primary biliary cirrhosis. These risk alleles in TNFSF15 and the altered expression of its gene product can serve as the common ground between these disorders by explaining at least some of the underlying processes that lead to a dysregulated immune response and subsequent chronic inflammation. Here, we aim to outline how the TNFSF15 gene is involved in the proliferation and cell fate of different populations of T cells and subsequently in the control of both pro-and anti-inflammatory cytokines. Furthermore, we summarize what is currently known of TNFSF15 control region variants, how they are associated with each mentioned disease, and how these variants can explain the autoimmune pathology of said diseases through altered TNFSF15 expression.
