Toll-like receptors (TLRs) are pattern-recognition receptors (PRRs) that sub-serve innate immunity by sensing and responding to perturbations of host homeostasis. The discovery and early functional characterization of TLRs were driven by the search for receptors that could link the detection of conserved and structurally unique molecules of invading microbes, called pathogen-associated molecular patterns (PAMPs), to the mobilization and induction of innate and adaptive immune defenses. Increasing evidence suggests that TLRs might have additional roles, including recognition and response to host-derived Danger-Associated Molecular Patterns (DAMPs) that can be triggered by infectious, as well as sterile stresses. However, in many circumstances, it is not yet clear whether this latter described role of TLRs is the consequence of direct interactions with host-derived DAMPs and/or mechanisms of cross-talk between resting or PAMP-activated TLR with other host signaling systems.
The goal of this Research Topic is to provide new insights and perspectives on the expanding role of TLR4 in homeostasis and immune pathology, focusing on mechanisms regulating activation of TLR4 in these diverse settings, the cross-talk with other receptor systems, and the functional consequences of these molecular processes. In this Research Topic, we welcome the submission of Review, Mini-Review, Opinion, and Perspective articles as well as descriptions of new experimental observations related to any of the following:
· Mechanisms regulating delivery of activating natural endotoxin, other natural and synthetic ligands to TLR4 and/or studies on molecular aspects of TLR4 activation.
· TLR4 activation, signaling, and cross-talk with other receptors: opioid receptors, TRPV1, PAR2, other PRRs.
· TLR4 activation during viral infections.
· TLR4-dependent aero-allergens.
· TLR4 activation and signaling in the central nervous system, including neurodegenerative inflammatory diseases and Alzheimer disease.
· TLR4 activation by heme.
· Protective vs pathologic roles of TLR4 in organ and tissue development, homeostasis, infection, and acute injury.
· TLR4-dependent activation of fibroblasts and roles in wound healing and persistent fibrosis.
· TLR4 activation by dietary fatty acids: obesity metabolic inflammation and obesity-induced insulin resistance.
· TLR4 in normal pregnancy and preterm birth.
· Cell-, tissue-, and/or stimulus-dependent TLR4 responsive gene signatures.
· Diverse and synergistic mechanisms of activation of TLR4.
· Progress and challenges in the development of synthetic, semisynthetic and natural TLR4 antagonists (inhibitors).
Toll-like receptors (TLRs) are pattern-recognition receptors (PRRs) that sub-serve innate immunity by sensing and responding to perturbations of host homeostasis. The discovery and early functional characterization of TLRs were driven by the search for receptors that could link the detection of conserved and structurally unique molecules of invading microbes, called pathogen-associated molecular patterns (PAMPs), to the mobilization and induction of innate and adaptive immune defenses. Increasing evidence suggests that TLRs might have additional roles, including recognition and response to host-derived Danger-Associated Molecular Patterns (DAMPs) that can be triggered by infectious, as well as sterile stresses. However, in many circumstances, it is not yet clear whether this latter described role of TLRs is the consequence of direct interactions with host-derived DAMPs and/or mechanisms of cross-talk between resting or PAMP-activated TLR with other host signaling systems.
The goal of this Research Topic is to provide new insights and perspectives on the expanding role of TLR4 in homeostasis and immune pathology, focusing on mechanisms regulating activation of TLR4 in these diverse settings, the cross-talk with other receptor systems, and the functional consequences of these molecular processes. In this Research Topic, we welcome the submission of Review, Mini-Review, Opinion, and Perspective articles as well as descriptions of new experimental observations related to any of the following:
· Mechanisms regulating delivery of activating natural endotoxin, other natural and synthetic ligands to TLR4 and/or studies on molecular aspects of TLR4 activation.
· TLR4 activation, signaling, and cross-talk with other receptors: opioid receptors, TRPV1, PAR2, other PRRs.
· TLR4 activation during viral infections.
· TLR4-dependent aero-allergens.
· TLR4 activation and signaling in the central nervous system, including neurodegenerative inflammatory diseases and Alzheimer disease.
· TLR4 activation by heme.
· Protective vs pathologic roles of TLR4 in organ and tissue development, homeostasis, infection, and acute injury.
· TLR4-dependent activation of fibroblasts and roles in wound healing and persistent fibrosis.
· TLR4 activation by dietary fatty acids: obesity metabolic inflammation and obesity-induced insulin resistance.
· TLR4 in normal pregnancy and preterm birth.
· Cell-, tissue-, and/or stimulus-dependent TLR4 responsive gene signatures.
· Diverse and synergistic mechanisms of activation of TLR4.
· Progress and challenges in the development of synthetic, semisynthetic and natural TLR4 antagonists (inhibitors).