Neurotrophins and asthma: novel insight into neuroimmune interaction

There is increasing evidence that neuronal dysfunction and dysregulation contribute to the pathogenesis of allergic asthma. Many functional aspects of peripheral neurons strongly depend on the activity of neurotrophins, a family of mediators originally defined by their neuronal growth activity. More recently, it has been discovered that neurotrophins (eg, nerve growth factor, brain-derived neurotrophin factor, and neurotrophin 3) have profound activities on various immune cells involved in the pathogenesis of allergic disease. Furthermore, immune cells themselves can produce neurotrophins under certain conditions, and the levels of neurotrophins, as well as neurotrophic activities, are strongly upregulated in allergic conditions. Animal data demonstrate that a number of pathomechanisms controlling allergic diseases are directly related to neurotrophin function, including the development of airway hyperresponsiveness. These findings now lead to a much better understanding concerning the regulatory loop between immunologic and neurogenic dysregulation. In this review we will provide an overview of how neurotrophins connect the pathobiology of airway inflammation and hyperresponsiveness, which are the hallmarks of allergic asthma.     

Neurotrophin-induced rapid enhancement of membrane potential oscillations in mesencephalic trigeminal neurons

We have proposed that neurotrophins, in addition to their trophic actions, act as neuromodulators in the adult central nervous system. As a first step to test this hypothesis, we examined in the adult rat slice preparation whether nerve growth factor and neurotrophin-3 are capable of altering the excitability of neurons of the mesencencephalic trigeminal nucleus. In contrast to vehicle pressure microapplication, which did not evoke changes in the electrophysiological properties of these neurons, neurotrophin application produced a significant increase in amplitude of the membrane potential oscillatory activity that is observed in these cells and a significant decrease in their threshold current. The latency of these effects ranged from 2 to 80 s and the duration ranged from 2 to 11 min. Neurotrophin-3 induced a decrease in input resistance and resting membrane potential in 58% of the cells; nerve growth factor induced a decrease in input resistance and resting membrane potential in 35% of the neurons. The spike configuration and action potential afterhyperpolarization potential remained unchanged following neurotrophin application. Tetrodotoxin blocked the membrane potential oscillatory activity of trigeminal mesencephalic neurons. Neurotrophin-induced effects were not blocked by the tyrosine kinase inhibitor K-252a, whereas IgG-192, an antibody directed to the neurotrophin low-affinity receptor, enhanced excitability, as did neurotrophins. These results demonstrate that neurotrophins are capable of producing a rapid increase in the excitability of trigeminal mesencephalic neurons and suggest that their effects may be mediated by low-affinity neurotrophin receptors.     

Neurotrophin-induced rapid enhancement of membrane potential oscillations in mesencephalic trigeminal neurons

We have proposed that neurotrophins, in addition to their trophic actions, act as neuromodulators in the adult central nervous system. As a first step to test this hypothesis, we examined in the adult rat slice preparation whether nerve growth factor and neurotrophin-3 are capable of altering the excitability of neurons of the mesencencephalic trigeminal nucleus. In contrast to vehicle pressure microapplication, which did not evoke changes in the electrophysiological properties of these neurons, neurotrophin application produced a significant increase in amplitude of the membrane potential oscillatory activity that is observed in these cells and a significant decrease in their threshold current. The latency of these effects ranged from 2 to 80 s and the duration ranged from 2 to 11 min. Neurotrophin-3 induced a decrease in input resistance and resting membrane potential in 58% of the cells; nerve growth factor induced a decrease in input resistance and resting membrane potential in 35% of the neurons. The spike configuration and action potential afterhyperpolarization potential remained unchanged following neurotrophin application. Tetrodotoxin blocked the membrane potential oscillatory activity of trigeminal mesencephalic neurons. Neurotrophin-induced effects were not blocked by the tyrosine kinase inhibitor K-252a, whereas IgG-192, an antibody directed to the neurotrophin low-affinity receptor, enhanced excitability, as did neurotrophins.These results demonstrate that neurotrophins are capable of producing a rapid increase in the excitability of trigeminal mesencephalic neurons and suggest that their effects may be mediated by low-affinity neurotrophin receptors.     

A neuronal subpopulation in the mammalian enteric nervous system expresses TrkA and TrkC neurotrophin receptor-like proteins

Increasing evidence suggests that, in addition to peripheral sensory and sympathetic neurons, the enteric neurons are also under the control of neurotrophins. Recently, neurotrophin receptors have been detected in the developing and adult mammalian enteric nervous system (ENS). Nevertheless, it remains to be established whether neurotrophin receptors are expressed in all enteric neurons and/or in glial cells and whether expression is a common feature in the enteric nervous system of all mammals or if interspecific differences exist. Rabbit polyclonal antibodies against Trk proteins (regarded as essential constituents of the high-affinity signal-transducing neurotrophin receptors) and p75 protein (considered as a low-affinity pan-neurotrophin receptor) were used to investigate the cell localization of these proteins in the ENS of adult man, horse, cow, sheep, pig, rabbit, and rat. Moreover, the percentage of neurons displaying immunoreactivity (IR) for each neurotrophin receptor protein was determined. TrkA-like IR and TrkC-like IR were observed in a neuronal subpopulation in both the myenteric and submucous plexuses, from esophagus to rectum in humans, and in the jejunum-ileum of the other species. Many neurons, and apparently all glial cells, in the human and rat enteric nervous system also displayed p75 IR. TrkB-like IR was found restricted to the glial cells of all species studied, with the exception of humans, in whom IR was mainly in glial cells and a small percentage of enteric neurons (about 5%). These findings indicate that the ENS of adult mammals express neuronal TrkA and TrkC, glial TrkB, and neuronal-glial p75, this pattern of distribution being similar in all examined species. Thus, influence of specific neurotrophins on their cognate receptors may be considered in the physiology and/or pathology of the adult ENS. Anat. Rec. 251:360–370, 1998. © 1998 Wiley-Liss, Inc.     

Neuroprotective actions of leptin on central and peripheral neurons in vitro

Neuronal cell death and its regulation have been extensively studied as an essential process of both neurodevelopment and neurodegenerative conditions. However it is not clear how circulating hormones influence such processes. Therefore we aimed to determine whether the anti-obesity hormone leptin could promote the survival of murine central and peripheral neurons in vitro. Thus we established primary neuronal cultures of dopaminergic midbrain neurons and trigeminal sensory neurons and induced cell death via either toxic insult or growth factor withdrawal. We demonstrate that leptin promotes the survival of developing peripheral and central neurons via activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3-kinase)/Akt/nuclear factor kappa B (NF-kappaB) -dependent signaling cascades. Specifically, leptin protects dopaminergic midbrain neurons from the apoptotic stimuli, tumor necrosis factor alpha (TNF-alpha) and 6-hydroxydopamine (6-OHDA). In addition, it promotes the survival of postnatal, but not embryonic, trigeminal sensory neurons following neurotrophin withdrawal. Our data reveal a novel neuroprotective role for leptin in the peripheral nervous system while expanding on the known anti-apoptotic role of leptin in the CNS. These findings have important implications for our understanding of neuronal viability.     

Neurotrophin secretion: current facts and future prospects

The proteins of the mammalian neurotrophin family (nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5)) were originally identified as neuronal survival factors. During the last decade, evidence has accumulated implicating them (especially BDNF) in addition in the regulation of synaptic transmission and synaptogenesis in the CNS. However, a detailed understanding of the secretion of neurotrophins from neurons is required to delineate their role in regulating synaptic function. Some crucial questions that need to be addressed include the sites of neurotrophin secretion (i.e. axonal versus dendritic; synaptic versus extrasynaptic) and the neuronal and synaptic activity patterns that trigger the release of neurotrophins. In this article, we review the current knowledge in the field of neurotrophin secretion, focussing on activity-dependent synaptic release of BDNF. The modality and the site of neurotrophin secretion are dependent on the processing and subsequent targeting of the neurotrophin precursor molecules. Therefore, the available data regarding formation and trafficking of neurotrophins in the secreting neurons are critically reviewed. In addition, we discuss existing evidence that the characteristics of neurotrophin secretion are similar (but not identical) to those of other neuropeptides. Finally, since BDNF has been proposed to play a critical role as an intercellular synaptic messenger in long-term potentiation (LTP) in the hippocampus, we try to reconcile this possible role of BDNF in LTP with the recently described features of synaptic BDNF secretion.     

Neuroimmunological findings in allergic skin diseases

PURPOSE OF REVIEW: Recent studies have gained widespread information about the complex regulation of genetic, environmental, immunologic, and pharmacologic factors that contribute to the development of allergic inflammatory skin diseases such as atopic dermatitis. Neuroimmune mechanisms, however, still remain to be elucidated. This review will focus on the interaction between the cutaneous immune and peripheral nervous system in allergic inflammatory skin such as atopic dermatitis. RECENT FINDINGS: Neuropeptides and neuropeptide-positive nerve fibres are prominently increased in lesions of atopic dermatitis. The density of nerve fibres is increased while peripheral nerve endings are in an active state of excitation. In this regard, neurotrophins particularly described for their functional role on nerve cells are also expressed in atopic dermatitis skin. In addition, neurotrophins modulate the functional role of eosinophils as main target effector cells in atopic dermatitis, as described recently. Interestingly, eosinophils are capable of neurotrophin as well as neuropeptide production itself, pointing to a bidirectional communication between neuronal cell populations and main target effector cells. SUMMARY: Neurotrophins and neuropeptides modulate both the functional activity of sensory neurons and immune cells. We have therefore developed the concept of a neuroimmune network between target effector cells and sensory nerves that links pathogenic events to dysfunctions of the cutaneous immune and peripheral nervous system in allergic inflammatory skin diseases.     

Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury

Neurotrophins are essential for development and maintenance of the vertebrate nervous system. Paradoxically, although mature neurotrophins promote neuronal survival by binding to tropomyosin receptor kinases and p75 neurotrophin receptor (p75(NTR)), pro-neurotrophins induce apoptosis in cultured neurons by engaging sortilin and p75(NTR) in a death-signaling receptor complex. Substantial amounts of neurotrophins are secreted in pro-form in vivo, yet their physiological significance remains unclear. We generated a sortilin-deficient mouse to examine the contribution of the p75(NTR)/sortilin receptor complex to neuronal viability. In the developing retina, Sortilin 1 (Sort1)(-/-) mice showed reduced neuronal apoptosis that was indistinguishable from that observed in p75(NTR)-deficient (Ngfr(-/-)) mice. To our surprise, although sortilin deficiency did not affect developmentally regulated apoptosis of sympathetic neurons, it did prevent their age-dependent degeneration. Furthermore, in an injury protocol, lesioned corticospinal neurons in Sort1(-/-) mice were protected from death. Thus, the sortilin pathway has distinct roles in pro-neurotrophin-induced apoptotic signaling in pathological conditions, but also in specific stages of neuronal development and aging.     

Neurotrophins and neurotrophin receptors in some neural crest-derived tumours (ganglioneuroma, phaeochromocytoma and paraganglioma)

AIM: This study analyses the occurrence and distribution of neurotrophins and their receptors in some types of tumours of neural-crest derived cells. METHODS AND RESULTS: Light microscopy immunohistochemistry associated with quantitative image analysis was used to study the expression of neurotrophins (nerve growth factor, brain-derived neurotrophic factor and neurotrophin (NT)-3) and their cognate receptors (p75(LNGFR), TrkA, TrkB and TrkC) in histologically defined ganglioneuroma, phaeochromocytoma and paraganglioma. The material was fixed in 10% formaldehyde, paraffin-embedded and processed for indirect peroxidase immunohistochemistry using a battery of poly- and monoclonal antibodies to detect neurotrophins and their receptors, as well as some neuronal, endocrine and glial cell markers. A subpopulation of cells in phaeochromocytomas and ganglioneuromas expressed NT-3, but not other neurotrophins, while in paragangliomas no neurotrophins were detected. Regarding neurotrophin receptors, all tumours lacked p75(LNGFR), except for the ganglionic part of a case of mixed phaeochromocytoma, whereas they displayed TrkA (two of two ganglioneuromas, six of nine phaeochomocytomas and three of four paragangliomas). Furthermore, TrkC was regularly detected in a neuronal subpopulation in ganglioneuroma. Interestingly, the percentage of neurones expressing TrkA and TrkC was increased with respect to normal tissues in ganglioneuromas, as well as the percentage of the area occupied by TrkA-immunoreactive cells in the phaeochromocytomas. CONCLUSION: The pattern of expression of neurotrophins and neurotrophin receptors in the analysed tumours basically matches that of sympathetic neurones, adrenal chromaffin cells and paraganglionic cells, and suggests responsiveness of these cells to neurotrophins. Nevertheless, the function of TrkA and TrkC in regulating the biology of these tumours, if any, remains to be elucidated.     

Factoring neurotrophins into a neurite-based pathophysiological model of schizophrenia

Neurotrophins are growth factors that, through variations in concentration and changes in receptor expression, regulate the formation of axons and dendrites during development and throughout adult life. Here we review these growth factors, particularly in the context of schizophrenia, a psychiatric disorder characterized by neurodevelopmental abnormalities. We first discuss emerging information derived from physiologically relevant organotypic cultures and in vivo studies regarding the effects of neurotrophins on the neuronal structure including pruning and GABAergic neurons. We then review postmortem studies of neurotrophin levels and their receptors in brains of individuals with schizophrenia, and compare them with what is known about neurotrophin effects on neuronal structure. This comparison indicates that only some neuropathological defects encountered in patients with schizophrenia can be explained by the single action of neurotrophins on dendrites and axons. However, we propose that a number of inconsistent findings and apparently unrelated results in the schizophrenia field can be reconciled if neurons are considered structurally plastic cells capable of extending and retracting dendrites and axons throughout life.     

Brain‐Derived Neurotrofic Factor and its Receptor TrkB are Present,but Segregated,Within Mature Cutaneous Pacinian Corpuscles of Macaca fascicularis

Some mechanoreceptors in mammals depend totally or in part on the neurotrophins brain‐derived neurotrophic factor (BDNF) and neurotrophin‐4 (NT‐4), and their receptor TrkB, for development and maintenance. These actions are presumably exerced regulating the survival of discrete sensory neurons in the dorsal root ganglia which form mechanoreceptors at the periphery. In addition, the cells forming the mechanoreceptors also express both neurotrophins and their receptors although large differences have been described among species. Pacinian corpuscles are rapidly adapting low‐threshold mechanoreceptors whose dependence from neurotrophins is not known. In the present study, we analyzed expression of TrkB and their ligands BDNF and NT‐4 in the cutaneous Pacinian corpuscles of Macaca fascicularis using immunohistochemistry and fluorescent microscopy. TrkB immunoreactivity was found in Pacinian corpuscles where it co‐localized with neuron‐specific enolase, and occasionally with S100 protein, thus suggesting that TrkB expression is primarily into axons but also in the lamellar cells and even in the outer core. On the other hand, BDNF immunoreactivity was found the inner core cells where it co‐localized with S100 protein but also in the innermost layers of the outer core; NT‐4 immunostaining was not detected. These results describe for the first time the expression and distribution of a full neurotrophin system in the axon‐inner core complex of mature Pacinian corpuscles. The data support previous findings demonstrating large differences in the expression of BDNF‐TrkB in mammalian mechanoreceptors, and also suggest the existence of a retrograde trophic signaling mechanism to maintain morphological and functional integrity of sensory neurons supplying Pacinian corpuscles. Anat Rec, 298:624–629, 2015. © 2014 Wiley Periodicals, Inc.     

Localisation of neurotrophin - containing cells in higher vertebrate intestine

Neurotrophins are structurally related proteins that regulate the development, differentiation and maintenance of many neuronal populations. In higher vertebrates (reptiles, birds and mammals) four neurotrophins have been found: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin (NT) 3 and NT4/5. In the gut, experimental data and the occurrence of neurotrophin receptors in intestinal neurons and endocrine cells suggest neurotrophin involvement in intestinal physiology. However, very few data are available regarding the cellular localization and distribution of neurotrophins in the gut. In this study we report the presence of NGF, BDNF and NT3 in neurons and endocrine cells of mouse, duck and lizard intestine. In particular, immunoreactivity to NGF was observed: (a) in both endocrine and nerve cells of mouse and duck intestine, (b) in endocrine cells of lizard gut. Immunoreactivity to BDNF was seen: (a) in nerve cells of mouse intestine, (b) in very few endocrine cells of mouse and duck intestine. Immunoreactivity to NT3 was detected: (a) in nerve cells of the mouse intestine, (b) in endocrine and nerve cells of duck and lizard gut. Our results, together with data previously reported, on the distribution of specific neurotrophin receptors, seem to suggest a possible paracrine/autocrine mechanism of neurotrophin action in both the enteric nervous system and endocrine cells.     

Immunohistochemical localization of neurotrophin receptor proteins in human skin

The target organs of neurotrophin-dependent sympathetic and sensory neurons, including the skin, synthesize and release neurotrophins, primarily NGF. Neurotrophins undergo retrograde axonal transport, and exert specific function in the perikarya of the responsive neurons. Moreover, evidence exists for an autocrine and/or paracrine function of neurotrophins in the skin. This study analyses the immunohistochemical localization of low (gp75) and high-affinity (gp140 trkA, gp145trkB and gp145trkC) neurotrophin receptor proteins in the human glabrous skin. We consider that the expression of neurotrophin receptors may be indicative of neurotrophin activity. Specific gp75 and gp140trkA-like immunoreactivity (IR) were observed highly co-localized in (1) epidermis, primarily in the basal keratinocytes; 2) sweat glands; (3) blood vessel walls, mainly in the muscular layer; (4) Schwann and perineurial cells of nerve trunks; (5) periaxonic cells forming sensory nerve formations (Meissner's and Pacini's corpuscles); (6) large axons of nerve bundles and of sensory corpuscles; gp145trkB-like and gp145trkC-like were found labelling nerve fibers and sensory nerve formations, as well as blood vessels and sweat glands, but not epidermic cells. The results suggest that, in addition to the well known neurotrophic functions, neurotrophins may also regulate unknown functions in non-nervous cutaneous cells, which are targets for neurotrophin-dependent sympathetic and sensory neurons.     

Herpes Simplex Virus Evolved to Use the Human Defense Mechanisms to Establish a Lifelong Infection in Neurons–A Review and Hypothesis

The review of recent studies using DNA microarrays shed new light on herpes simplex virus (HSV) replicative cycle, the response of immature dendritic cells (DCs) to pathogens and the response of neurons in trigeminal ganglia to virus reactivation. These studies provided a better understanding of the molecular biology of HSV during infection, latency and reactivation. The research on the sensory trigeminal neurons and the neuronal axons (type C fibers) that transverse the skin basal membrane, enter the skin epidermis and interact with the cell membrane of the skin resident immature DCs provided an insight on the connection between the nervous system and the host immune system. Based on these studies a hypothesis is presented suggesting that HSV evolved to use the human host defense systems (pain signals, the immune system cells and sensory neurons) to ensure its entry from the skin epithelium into the sensory neurons. Reactivated HSV in the neurons utilizes the same host defense systems to return to the skin epithelium.     

Specification of sensory neurons occurs through diverse developmental programs functioning in the brain and spinal cord

Background : Vertebrates possess two populations of sensory neurons located within the central nervous system: Rohon‐Beard (RB) and mesencephalic trigeminal nucleus (MTN) neurons. RB neurons are transient spinal cord neurons whilst MTN neurons are the proprioceptive cells that innervate the jaw muscles. It has been suggested that MTN and RB neurons share similarities and may have a common developmental program, but it is unclear how similar or different their development is. Results : We have dissected RB and MTN neuronal specification in zebrafish. We find that RB and MTN neurons express a core set of genes indicative of sensory neurons, but find these are also expressed by adjacent diencephalic neurons. Unlike RB neurons, our evidence argues against a role for the neural crest during MTN development. We additionally find that neurogenin1 function is dispensable for MTN differentiation, unlike RB cells and all other sensory neurons. Finally, we demonstrate that, although Notch signalling is involved in RB development, it is not involved in the generation of MTN cells. Conclusions : Our work reveals fundamental differences between the development of MTN and RB neurons and suggests that these populations are non‐homologous and thus have distinct developmental and, probably, evolutionary origins. Developmental Dynamics 243:1429–1439, 2014. © 2014 Wiley Periodicals, Inc.     

NGF-mediated sensitization of the excitability of rat sensory neurons is prevented by a blocking antibody to the p75 neurotrophin receptor

Nerve growth factor (NGF) can play a causal role in the initiation of hyperalgesia. Recent work demonstrates that NGF can act directly on nociceptive sensory neurons to augment their sensitivity to a variety of stimuli. Based on the existing literature, it is not clear whether this sensitization is mediated by the high-affinity TrkA receptor or the low-affinity p75 neurotrophin receptor. We examined whether a blocking antibody to the p75 neurotrophin receptor can prevent the NGF-induced enhancement of excitability in capsaicin-sensitive small-diameter sensory neurons that have been isolated from the adult rat. In this report, pretreatment with the p75 blocking antibody completely prevents the NGF-induced increase in the number of action potentials evoked by a ramp of depolarizing current as well as the suppression of a delayed rectifier-type of potassium current(s) in these neurons. Although the sensitization by NGF was blocked, the antibody had no effect on the capacity of ceramide, a putative downstream signaling molecule, to either enhance the excitability or inhibit the potassium current. These results indicate that NGF can increase the excitability of nociceptive sensory neurons through activation of the p75 neurotrophin receptor and its consequent liberation of ceramide from neuronal sphingomyelins.     

The quest for remyelination: a new role for neurotrophins and their receptors

The formation of myelin is dependent on a reciprocal and intimate relationship between neurons and the myelin-forming glia. Recently, the neurotrophin family of growth factors has been shown to regulate the complex cell-cell interactions that control myelination. Neurotrophins and their receptors influence myelin formation via two distinct mechanisms, either by acting on the neurons, changing the axonal signals that control myelination, or by acting directly on the myelin-forming glia. In this review, we will discuss research highlighting the ability of neurotrophins to both promote and inhibit the myelination process. As reflected in the work presented here, these effects are dependent on a delicate balance of which neurotrophins are expressed, and what receptors are activated. Additionally, we examine an emerging model in which the growth factors that promote the early survival and differentiation of particular sets of neurons later play important roles as key regulators in glial development. Characterizing the temporal expression and the cellular targets of neurotrophins, both during development and after injury, represents a pivotal step in developing a greater understanding of the myelination process, contributing to the development of effective treatments for demyelinating conditions. We conclude this review by discussing the potential for neurotrophins as therapeutics in the quest for remyelination.