Nerve Growth Factor and Inflammation: A Complex Bidirectional Interaction

Nerve Growth Factor and Inflammation: A Complex Bidirectional Interaction
OVERVIEW ARTICLE

The nervous and immune systems share common functions: both are involved in adapting the body to the environment and in maintaining homeostasis.

Because they are the two major adaptive systems of the body it is not surprising that they have developed common strategies: both are able to sense external and internal variations, which are signaled to specialized cells causing the activation of specific and rapid responses.

Through these well orchestrated responses the two systems not only restore homeostasis but retain the memory of the “danger” so that faster and more specific reactions will be triggered after subsequent similar challenges to homeostasis. To be able to orchestrate a strictly integrated response, the two systems should act simultaneously, communicate with each other and work together to eliminate danger and restore homeostasis [1]. Thus, for  a  more efficient control of the internal environment, cross-talk between the nervous and immune systems, based on close anatomical connections [2,3], common chemical signals and specific receptors [4-6], is needed to sense challenge to the host, monitor immune activity and activate neuronal pathways and regulatory loops [7,8].

Among the growing number of molecules known to be involved in both neuronal and immune modulation, Nerve Growth Factor (NGF) seems to have a role in this complex network of bi-directional signals between the nervous and immune systems.

NGF and peripheral nervous system: regulation of innervation and neuropeptide synthesis

 1. NGF and its receptors

NGF is the best-characterized member of the neurotrophin family, a group of proteins that have similar structures and functions [9]. The amino acid and messenger RNA sequences of this neurotrophin have been categorized and indicate that NGF is a highly conserved molecule that shares considerable homology within different species [10,11].

The biological effects of NGF are directly dependent on its initial binding to cell surface receptors: TrkA and p75NTR [12]. TrkA is a transmembrane tyrosine kinase of 140 kD; it is the specific receptor for NGF and is phosphorylated on tyrosine residues after binding of its ligand.  p75NTR is a 75 kD glycoprotein that belongs to the TNF-receptor superfamily and is known as the pan-neurotrophin receptor because it can bind not only NGF but also other neurotrophins with similar affinity. NGF signalling through TrkA elicits the majority of the actions ascribed to NGF. Through the binding to its receptors NGF triggers numerous intracellular signalling cascades:  the major pathways activated by NGF through TrkA are Ras, PI3-kinase, PLC-gamma1 and their downstream effectors, while the p75NTR-mediated signaling pathways are Jun kinase signaling cascade, NF-kappaB activation and ceramide generation [13].

2. NGF effects on peripheral neurons in embryonic and adult life

NGF was identified for its ability to sustain survival of sympathetic and sensory neurons during embryonic development. The pioneering studies of Levi-Montalcini showed that during development, limited amounts of NGF produced in target organs are responsible for the proliferation, differentiation and survival of peripheral autonomic and sensory neurons [14]. The neutralization of NGF with anti-NGF antibodies during fetal life results in irreversible destruction of the sympathetic ganglia and in a marked reduction in sensory neurons [14]. The critical role of NGF in the development of the peripheral nervous system has been further confirmed by studies using knockout mice [15-18]. ngf -/- and trkA -/- mice have almost no sympathetic ganglia and a dramatically depleted population of sensory neurons in dorsal root ganglia (DRG). The neuronal loss is selective and affects small peptidergic neurons that mediate pain. In adult life, while sympathetic neurons continue to depend on NGF for their survival, there is a shift in the role of NGF in the sensory neurons. While NGF is no longer indispensable for their survival, it is crucial for the maintenance of a differentiated phenotype. In these mature sensory neurons, as well as in sympathetic neurons, NGF dynamically controls neurotransmitter and neuropeptide synthesis. In sympathetic neurons the levels of norepinephrine are regulated by NGF through selective induction of tyrosine hydroxylase (TH) [19]. In DRG the expression of Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP) is under NGF control [20,21] and in vivo deprivation of NGF, as a result of nerve transection or anti-NGF treatment, causes a marked decrease in SP and CGRP synthesis in DRG [22]. In adult life, a constant supply of NGF from the innervation field influences the neuronal plasticity that allows the adult nervous system to modify its structure and functions in response to stimuli. The constitutive synthesis of NGF in adult tissues correlates with innervation density and influences cell body size, axonal terminal sprouting, dendritic arborization, induction or inhibition of neuropeptides and neurotrasmitters or transmitter-producing enzymes [19-26]. In mice that overexpress NGF in epithelial structures [27-29], there is a dramatic increase in axon numbers, alteration of fiber distribution, increased branching and modification of the neuronal phenotype in target organs. The spleen of the transgenic animals and the peripheral lymph nodes, by draining lymph from NGF over-expressing tissues, show different innervation patterns and fiber density and these characteristics are more pronounced in animals with higher levels of NGF expression [30].

Inflammatory stimuli influence NGF production in tissues

Numerous studies have shown that during the inflammatory process there is a localized increase in NGF at the sites of inflammation.  Increased NGF concentrations, which closely follow the course of disease, were initially found  in the cerebrospinal fluid of Multiple Sclerosis patients [31], in the synovial fluids of Rheumatoid Arthritis patients [32] and in the sera of Systemic Lupus Erythematosus (SLE) patients [33,34]. NGF mRNA expression and protein levels increase in animal models of inflammation such as Freund’s adjuvant-induced and carragenin-induced arthritis [35,36], in NZB/W mice, a spontaneous model of human SLE [37], and in experimental autoimmune encephalomyelitis (EAE) [38]. NGF enhancement seems to be a common feature of many other inflammatory diseases [39] such as interstitial cystitis [40,41], allergic asthma [42,43], vernal keratoconjunctivitis [44], Crohn’s disease and colitis [45,46], psoriasis [47,48] and atopic dermatitis [49]. The data obtained from all these in vivo studies have clearly indicated that NGF synthesis is up-regulated during an inflammatory process and that inflammation and tissue damage generate mediators that control the local concentration of NGF. Inflammatory cytokines such as IL-1beta, TNF-alpha and IL-6 are able to modify the basal production of NGF in the organism and induce the synthesis of NGF in a variety of cell types and tissues (Figure 1).

nerve growth factor and inflammationFigure 1. Inflammatory stimuli influence NGF production in tissues. This effect appears to be mediated by a direct action on immune cells (reduced migration and antigen presentation and increased production of IL-10). Inflammatory process and tissue damage generate mediators that control the local concentration of NGF. The basal production of NGF in the tissue is enhanced and a variety of cell types is induced to synthesize NGF in response to inflammatory cytokines (i.e. IL-1 beta, TNF-alpha, IL-6), prostaglandins and histamine.

In fact, both IL-1beta and TNF-alpha can induce the synthesis of NGF in neurons [50,51], Schwann cells [52], astrocytes [53], microglia [54], enteric glial cells [55], epithelial cells [56], fibroblasts [57,58], mesangial cells [59], smooth muscles [60], adipocytes [61,62], sinoviocytes [63,64], keratinocytes [65] and endothelial cells [66,67]. Similar induction of NGF production in many cell types has been demonstrated in vitro using IL-6 [68-70].  Other inflammatory mediators such as prostaglandins [71,72] and histamine [73] have also been shown in vitro to induce NGF production in certain cell types.

In addition, immune cells involved in innate and acquired immunity show a basal expression of NGF, whose synthesis is dynamically regulated and enhanced in activated cells after stimulation with specific antigens and cytokines [74-78]. Activation of NF-kappaB pathways seems to play a pivotal role in regulating NGF expression in B lymphocytes [79].

Since the endogenous levels of NGF are substantially increased in the inflamed tissues, it is not surprising that during the inflammatory process the innervation of these tissues is not static [80]. Inflammation induces marked alterations in nerve fiber distribution and influences the phenotype of innervating neurons inducing the expression of neurotransmitters, neuromodulators, ion channels, G protein-coupled receptors and growth-associated structural proteins [80,81]. During inflammation the neuronal phenotype can even be modified, altering the amount or type of neurotransmitters produced and stored in nerve terminals. Afferent nerves that normally do not express tachykinins are induced to synthesize and use these neuropeptides [82]. Peripheral inflammation leads to an increased sensitivity to pain: the properties of the somatosensory neurons change so that the pain threshold decreases, noxious stimuli evoke more acute and  prolonged pain (hyperalgesia) and normally innocuous stimuli became painful (allodynia).

This peripheral sensitization increases the firing of nociceptors and the intense stimulation induces the release from nerve endings of neuropeptides that can influence a variety of immune cell functions. One of the best-known neuroimmune mechanisms involving sensory neuropeptides is a phenomenon known as neurogenic inflammation: the release of neuropeptides by sensory nerves induces vasodilatation, plasma extravasation, promotes leukocyte chemotaxis and phagocytosis [83], and directly affects the release of inflammatory mediators from immune cells such as mast cells and macrophages [84]. In the mucosae and in lymphoid organs, sensory fibers are in close contact with the cell membranes of keratinocytes, mast cells, macrophages, Langherans cells and endothelial cells in what has been defined a “neuroimmune junction” [5]. The release of neuropeptides from nerve endings induces in these cells synthesis of inflammatory mediators and cytokines, and affects their functions. While SP has a clearly demonstrated pro-inflammatory role [85], CGRP, which is often co-localized with SP in nerve endings, can also have an inhibitory action. CGRP is a potent inhibitor of mitogen and antigen-stimulated proliferation of T-cells [86], antigen presentation by antigen presenting cells [87]  and cytokine synthesis [88].

The localized increased production of NGF in inflammatory conditions is considered to have a central role in the induction of hypersensitivity and inflammatory pain [89-91]. In vivo studies have shown that during the inflammatory process the localized increase in NGF induces modification of gene expression in dorsal root ganglia that can be prevented using anti-NGF antibodies [92]. The neuronal phenotypic changes produced by NGF during inflammation include elevation of neuropeptides which amplify sensory input signals in the spinal cord and augment neurogenic inflammation in the periphery. NGF changes excitability of the neurons by increasing the expression of transmitters and tachykinins [93], receptors such as the capsaicin receptor TRPV1 [94,95], sensory neuron specific sodium channels [96], and by upregulating growth-related molecules which promote terminal sprouting and lead to a hyper-innervation of injured tissue [97-99].

NGF influences development and differentiation of immune cells

The release from sensory nerve endings of neuropeptides, which affect immune cell functions, represents a direct means for the nervous system to regulate immune response. Since NGF directly induces the expression of neuropeptides and neurotransmitters in peripheral neurons, by directly acting on their promoters or neurotransmitter-producing enzymes. One of the possible mechanisms by which NGF may affect the immune response in a tissue is through the regulation of neurotransmitter and neuropeptide production.

Studies of inflammatory disorders characterized by enhanced NGF production, abnormal activation of the immune system and increased production of cytokines, suggest that NGF can also be directly involved in regulating  the immune response. This hypothesis has gained support from findings demonstrating the expression of the specific NGF receptors in lymphoid organs and in purified immune cell populations.

The expression of NGF receptors has been found in primary (thymus, bursa of Fabricius, bone marrow) and secondary (spleen, tonsils, lymph nodes) lymphoid organs [100-102], and is raised during lymphocyte precursor migration but declines during post-natal life. NGF is also produced in primary lymphoid organs [100,103] and it is possible that NGF localized synthesis may contribute to create the micro-environment for the differentiation of hematopoietic stem cells [104,105]. In vitro NGF stimulates the functional activity of thymic epithelial cells inducing the expression of adhesion molecules important for thymocyte-thymic epithelia interaction and up-regulates the expression of thymopoietic factors such as IL-7, GM-CSF and SDF-1 [106].

TrkA expression has been described in hematopoietic precursors [107] and NGF acts as a survival factor [108,109] and a colony-stimulating factor for human and murine myeloid progenitor cells, inducing basophil and mast cell differentiation [110-113]. Human CD34+ hematopoietic stem cells are characterized by an elevated expression of TrkA and by simultaneous expression and production of their own NGF [114]. The expression of TrkA observed in hematopoietic precursors is maintained during lineage differentiation and mature immune cells express TrkA, albeit less abundantly. A gradient of TrkA and NGF expression exists with age and is highest in cord  blood CD34+ cells, reduced in cord blood mononuclear cells and minimal in mononuclear cells isolated from adult peripheral blood [114]. Changes in TrkA expression observed in immature and mature immune cells may indicate a different requirement for NGF, depending on the immune cell state of maturity and functional activity of these cells.

NGF and the immune response

NGF receptor expression has been studied in purified immune cell populations. TrkA expression has been demonstrated in mononuclear cells [115], thymocytes [100], human B and T lymphocytes  [74, 75, 116,117 ], monocytes [77, 118], mast cells [119],  basophils [120]  and  eosinophils [121]. These cells have a basal expression of TrkA in resting condition, but after antigenic or mitogenic stimulation, when strong functional activity is necessary, they  upregulate TrkA expression [74,75,77,117,118].

The discovery that the majority, if not all, of the immune cells express specific receptors for NGF and were potentially able to respond to it lent considerable impulse to studies of the influence of NGF on immune functions. After the first study demonstrating that the injection of NGF in newborn rats caused an increase in the number and size of mast cells [122], which was the earliest evidence of an effect of NGF on immune cells and outside the nervous system, numerous in vitro studies have shown that NGF is able to exert a wide spectrum of effects on immune cells (Figure 2).

Figure 2. NGF effects on purified immune cell populations The expression of TrkA, the specific receptor that mediates the biological activity of NGF, characterizes immune cells. The expression of TrkA observed in hemopoietic stem cells is maintained during lineage differentiation and in mature immune cells. Due to the presence of TrkA, immune cells are potentially able to respond to NGF and a considerable number of in vitro studies have demonstrated numerous NGF effects on immune functions.

Figure 2. NGF effects on purified immune cell populations. The expression of TrkA, the specific receptor that mediates the biological activity of NGF, characterizes immune cells. The expression of TrkA observed in hemopoietic stem cells is maintained during lineage differentiation and in mature immune cells. Due to the presence of TrkA, immune cells are potentially able to respond to NGF and a considerable number of in vitro studies have demonstrated numerous NGF effects on immune functions.

An NGF effect that seems to be common to the majority of cell populations analyzed is its dose-dependent influence on the survival of hematopoietic stem cells and mature, differentiated cells [74,108,109, 123,124]. The viability-sustaining activity of NGF has been attributed to its effect on the induction of anti-apoptotic proteins such as Bcl-2.

1. NGF effects on granulocytes and mast cells

In general, in vitro studies on granulocytes and mast cells have shown that NGF can potentiate their responses to inflammatory stimuli, but its effects differ depending on the cell type analyzed. In activated basophils, NGF enhances the synthesis of lipid mediators  (leukotrienes) in response to inflammatory stimuli [125,126], and together with IL-3 and  IL-33, acts as cofactor to induce the release of histamine and enhance the response to IgE in both basophils and mast cells [127-131]. In immature mast cells NGF causes a dose-dependent up-regulation of tryptase and IgE receptors [132]. In mature mast cells the addition of NGF after stimulation with lysophosphatidylserine induces and enhances cyclooxygenase2 (COX2) expression and the generation of prostaglandin D2 [133]. NGF synergizes with lipopolysaccharide (LPS) for the induction of IL-6 and this effect is abolished by COX2 inhibitors [134]. It has been reported that NGF alone can enhance mRNA expression in mast cells for IL-1alpha, IL-1beta, IL-6 and IL-10, but this could be a result of cellular stress during the isolation procedure because the effect was abolished after pre-incubation in complete medium before the addition of NGF  [124]. In contrast to its effect on basophils,  NGF tends to suppress leukotriene formation in eosinophils [125]. However, NGF seems to stimulate the production of IL-4 [121], influences the release of eosinophils peroxidase and enhances cytotoxic activity [135].

As for mast cells [123,124], NGF also enhances, in a dose-dependent way, survival also of eosinophils [135]  and neutrophils [136] by suppressing apoptosis, an effect abolished by anti-NGF antibody treatment. In neutrophils, in addition to its survival effect, NGF enhances superoxide production after cell activation with zymosan and stimulates phagocytosis [136]. After preliminary studies in the 80s’ that showed that NGF was a chemoattractant factor for granulocytes [137,138], more recent studies have shown that mast cells [139], eosinophils and neutrophils [140,141]  are influenced by the presence of NGF at the site of inflammation. This effect does not seem to be a direct one, but is probably regulated by neuropeptides and other mediators.

In the bronchoalveolar lavage fluid of transgenic mice overexpressing NGF in the lungs, there is an increased number of eosinophils and IL-5 concentration after allergen sensitization and challenge. This difference between transgenic and wild type mice was completely abolished using receptor antagonists of Substance P and Neurokinin A receptors [140]. Local administration of NGF in rat skin induced neutrophil accumulation and this appears to be mediated by NGF induction of  adhesion molecules (i.e. ICAM-1) in endothelial cells [142]. The use of anti-ICAM-1 antibodies blocked neutrophil accumulation in NGF-treated skin, suggesting that NGF has primarily an activating effect on endothelial cells, resulting in the accumulation of neutrophils [142]. Abnormally decreased migration of  neutrophils has been reported in patients with congenital insensitivity to pain with anhidrosis (CIPA), a rare genetic disease characterized by mutation of the TrkA gene [143]. All these data suggest that the presence of NGF is pivotal to cell recruitment at the inflammation site, though the mechanisms and mediators involved still remain to be clarified.

2. NGF effects on B and T lymphocytes

The studies on NGF effects on lymphocytes have shown that NGF is able to potentiate the proliferative response of B and T-cells to several mitogens [144]. The NGF dose-dependent increase in DNA synthesis is inhibited by anti-NGF antibodies. The addition of NGF induces interleukin-2 receptors in mature lymphoid cells and the proliferative response is augmented in B-cells when NGF is added together with IL-2 [116]. Although CD4+ lymphocytes also express TrkA receptors [117], few data on these cells are available, while more numerous studies have focused on B lymphocytes. B-cells express TrkA [74] and the binding of NGF to this receptor activates intracellular pathways and nuclear factors in a manner similar to that described in neurons [145-147]. Abolition of TrkA function in knock out mice models [148] or in CIPA patients results in altered differentiation and survival of  B lymphocytes [149]. Different studies using B cells obtained from healthy controls or animal models stimulated with a variety of stimuli, with or without the presence of T cells, have shown that NGF can influence the production of IgM and IgG (especially IgG4) [150,151]. Altogether these results support the conclusion that NGF stimulates B cell immune responses. However, it has also been reported that  NGF and anti-CD40 decrease immunoglobulin secretion in a dose-dependent manner [152,153]. Moreover, in mice selectively lacking TrkA expression in non-neuronal tissues, increased IgM, IgG1 and IgG2 levels have been described [148]. These data are in contrast with those described above and with the findings showing that NGF is a survival factor for memory B cells [74], promotes the differentiation of B-cells into immunoglobulin-secreting plasma cells [150] and influences plasma cell survival [154]. These evident contradictions lend support to the conclusion that a clear understanding of the physiological and pathological role of NGF on B cells is still lacking.

3. NGF effects on monocytes/macrophages and dendritic cells

Monocytes and macrophages express TrkA and p75NTR, while differentiated dendritic cells lose TrkA and maintain only p75NTR expression [77,118,155]. All these cells enhance [77,118] or re-express TrkA [156]  in the presence of inflammatory stimuli (i.e. classically LPS). NGF protects monocytes from apoptosis induced by UVB radiation or gliotoxin, by inducing the expression of anti-apoptotic proteins Bcl-2, Bcl-xl and Bfl-1 [155]. In vitro migratory properties are affected: in macrophages, NGF increases CXCR4 expression and chemotactic response to sub-optimal CXCL-12 concentration [157]. Inflammatory macrophages isolated from the peritoneum after stimulation and then treated with NGF show an  increase in phagocytosis, an enhanced parasite-killing activity and an induction of  IL-1beta [158]. NGF can also induce TNF-alpha  secretion and a modest increase in nitric oxide (NO) production in macrophages [159], but this latter effect is strongly amplified when cells are pre-treated with interferon-gamma. NGF addition promotes LPS-induced maturation of dendritic cells and induced secretion of inflammatory cytokines [156]. Dendritic cells derived from allergic donors and stimulated with LPS and CD40 ligand produce more IL-6 in response to NGF while the effect of NGF on  dendritic cells generated from healthy donors is to induce more IL-10 production [156]. Consistent with this finding is the fact that NGF deprivation in LPS-treated monocytes significantly decreases IL-10 synthesis [160].

4. NGF induces neuropeptide production in immune cells

In addition to the induction of inflammatory mediators and cytokines, NGF can also induce in immune cells the synthesis of neuropeptides with immunomodulatory functions. Similarly to its effect on neuronal cells, NGF can induce NPY expression in T lymphocytes [161] and regulates the expression and release of CGRP in human B lymphocytes [162] and monocytes [160,163]. The synthesis of CGRP is enhanced after LPS stimulation and this up-regulation is abolished when NGF is neutralized [160].

The binding of CGRP to its specific receptors on monocytes activates a cAMP-PKA pathway that inhibits pro-inflammatory cytokine synthesis [164] and up-regulates production of IL-10 in LPS-stimulated cells. Using CGRP receptor antagonists in LPS-treated monocytes, the expression of membrane molecules involved in antigen presentation, such as HLA-DR and CD86, is increased [160]. By inducing CGRP and IL-10 production, NGF can reduce the antigen-presenting capacity and co-stimulatory function of monocytes and may contribute to the down-regulation of T-cell responses.

These data suggest that at least some of the NGF effects described until now are not directly dependent on NGF itself, but rather are regulated by intermediate mediators whose synthesis is under NGF control. There are already numerous data available suggesting that neuropeptides such as SP, CGRP, NPY, and VIP, whose synthesis is  induced by NGF in neurons and probably in many more immune cells than we are currently aware of, play a key role in regulating inflammatory and anti-inflammatory responses and in maintaining homeostasis [85,165-167].

NGF in vivo anti-inflammatory action

From the in vitro data it can be concluded that NGF maintains immune cells in a “state of alert” to potential danger signals. Indeed, the in vitro data show that NGF helps to mount a faster and stronger inflammatory response. NGF by itself does not seem to induce inflammatory and immune responses efficiently but in the presence of specific stimuli, it enhances mediator release and cytokine production and activates functions of innate immune cells.
However, at present some of the data obtained in vivo are not consistent with this conclusion, and the role of NGF in vivo is rather different from what might have been expected from in vitro studies. As will be shown in the next paragraph, the reason why NGF production is increased during inflammation and how this enhanced concentration affects the immune and inflammatory responses are far from being understood.

The idea that NGF plays a much more complex role and may be involved in multiple mechanisms regulating the immune response has emerged from studies on experimental models of EAE. In marmoset EAE, intraventricular administration of NGF one week after disease induction with myelin oligodendrocyte glycoprotein (MOG) immunization, delays the onset of clinical EAE and prevents the full development of histological lesions in the central nervous system (CNS). In the brain of NGF-treated animals, the number and size of inflammatory infiltrates are reduced and demyelination is minimal [168]. The production of interferon-gamma by the T-cells infiltrating the brain is reduced, while production of IL-10 is enhanced in NGF-treated animals [168]. Similar results were obtained in a murine EAE model. Intraperitoneal injections of NGF starting one day after immunization with myelin basic protein (MBP) or after adoptive transfer of encephalitogenic T-cells led to a delayed onset, decreased clinical signs of the disease and enhanced survival of the animals [169]. In a T-cell transfer model of EAE, myelin basic protein-specific CD4+ T-cell clones were transduced with recombinant retrovirus encoding for NGF and used to induce EAE in rats [170]. These MBP clones producing NGF did not induce EAE although the transduction did not affect cytokine production or antigen reactivity. When the pathogenetic wild-type MBP clones were injected together with the NGF-transfected clones, the rats developed a very mild disease with no or only minor clinical signs [170]. Analysis of the brains showed a reduction in inflammatory cells crossing the endothelial brain-blood barrier (BBB), with the number of activated macrophages being especially decreased. In a co-culture system with monocytes and endothelial BBB, the addition of NGF interfered with monocyte migration through the activated endothelium [170]. Complementary effects are observed in an EAE rat model, in which NGF deprivation results in an exacerbated brain inflammation and more severe clinical signs [171].

The data obtained in different EAE models thus support an anti-inflammatory role of NGF in CNS immune-mediated inflammation. In these models the  administration of NGF seems to exert its effects directly on  immune cell activity: inhibition of  monocyte  migration and antigen presentation, altered  T-helper balance, down-regulation of IFN-gamma synthesis and up-regulation of  the anti-inflammatory cytokine  IL-10 (Figure 3).

Figure 3. Possible mechanisms for NGF in vivo anti-inflammatory action Administration of NGF in experimental models of inflammation inhibits monocyte migration and antigen presentation, alters T-helper balance and down-regulates IFN-γ. Some of these NGF effects can be mediated by IL-10 and CGRP. NGF induces the synthesis of the anti-inflammatory cytokine IL-10 in immune and epithelial cells and the expression of CGRP in peripheral neurons and antigen presenting cells. Both IL-10 and CGRP can dampen the immune response essentially by affecting antigen presentation in APCs, reducing T-lymphocytes proliferation and inflammatory cytokine synthesis. Thus, the reported enhancement of NGF in inflammatory diseases might represent a physiological mechanism activated for fine-tuning anti-inflammatory responses.

Figure 3. Possible mechanisms for NGF in vivo anti-inflammatory action. Administration of NGF in experimental models of inflammation inhibits monocyte migration and antigen presentation, alters T-helper balance and down-regulates  IFN-γ. Some of these NGF effects can be mediated by IL-10 and CGRP. NGF induces the synthesis of the anti-inflammatory cytokine IL-10 in immune and epithelial cells and the expression of CGRP in peripheral neurons and antigen presenting cells. Both IL-10 and CGRP can dampen the immune response essentially by affecting antigen presentation in APCs, reducing T-lymphocytes proliferation and inflammatory cytokine synthesis. Thus, the reported enhancement of NGF in inflammatory diseases might represent a physiological mechanism activated for fine-tuning anti-inflammatory responses.

Similarly, in experimental models of colitis it has been shown that NGF production remains elevated in the tissue until colon inflammation subsides [172]. Neutralization of NGF by pre-treatment with anti-NGF antibodies before the induction of colitis causes a significant increase in the severity of clinical signs with more extended lesions and ulcers, together with an increase in the number of infiltrating neutrophils and macrophages [173]. Also in this experimental model, the increase in NGF correlates with the enhancement of IL-10 [172], possibly because intestinal epithelial cells NGF and IL-10 are able to regulate each other’s expression [174], as shown in vitro.

In addition to the induction of the anti-inflammatory cytokine IL-10, a number of observations point to the involvement of other mechanisms in the in vivo anti-inflammatory effects of NGF. In the colitis model, enhanced tissue inflammation caused by NGF neutralization is associated with a marked reduction in CGRP content in the gut [175]. Moreover,  the ablation of sensory fibers results in a marked severity of inflammation in acute and chronic models of experimental colitis  and in both cases the decrease in CGRP content or  its inhibition in the colon using CGRP receptor antagonist aggravates experimental colitis [176]. Functional sensory neurons and their neuropeptides (i.e. CGRP) are probably involved in the in vivo action of NGF. The endogenous NGF produced in vivo at the site of inflammation thus represents a critical link between nervous and immune cells.

This hypothesis is supported by studies on a mouse model in which the animal’s skin received Ultraviolet B (UVB) irradiation. UVB, as well as causing edema and erythema, induces systemic suppression of contact hypersensitivity (CHS) responses and NGF, together with  nerves and neuropeptides, seems to play a relevant role in this phenomenon. In mouse epidermis, UVB irradiation up-regulates NGF expression, which peaks after 12 hours [177].  Anti-NGF antibodies administered prior to UVB irradiation abrogate the systemic suppression of CHS in mice [178]. Similarly, in normal mice, the CHS response was inhibited by NGF pre-treatment of the skin before trinitrochlorobenzene (TNCB) sensitization [178]. Moreover, when mice were treated with capsaicin, which depletes nerve endings of sensory neuropeptides, pre-incubation with NGF was not effective in suppressing CHS response [178].  Also in this model NGF-induced synthesis of CGRP seems to represent a key mediator for the control of immune cell activity and for balancing pro- and anti-inflammatory responses. In UV-induced tolerance, the induction of CGRP synthesis in cutaneous sensory C-fibers after UV radiation [179] is regulated by keratinocyte-derived NGF [178]. In vivo CGRP administration dampens the immune response essentially by affecting antigen presentation in a variety of antigen-presenting cells (APCs) [86, 87,180,181]. This inhibitory activity of CGRP seems to be mediated through inhibition of the NF-kappaB pathway [182] and a rapid up-regulation of inducible cAMP early repressor (ICER) [164,183], which causes premature repression of inflammation-induced transcriptional activity.

Thus, the ability of NGF in vivo to regulate production and release of sensory neuropeptides seems to be a key factor not only in keeping the defense system active (i.e. through SP) but also in activating inhibitory pathways that limit inflammation. Indeed, there is an increasing volume of data from in vivo models of inflammation showing that integrity of the peripheral nervous system is essential for the activation of an anti-inflammatory  feedback circuit [184-188]. A typical example of nerve damage leading to uncontrolled tissue inflammation is given by cutaneous infections and altered immune responses in diabetes. In both humans and animal models of drug-induced diabetes, impaired production of NGF is responsible for the reduction in cutaneous innervation. In animal models, the exogenous administration of NGF, while improving nerve functions and restoring innervation in the skin [189],  normalizes the diabetes-impaired response to wound healing by decreasing neutrophil accumulation and increasing re-epithelialization and matrix density [190]. Recent data obtained in transgenic mice overexpressing NGF indicate that these animals, while having increased number of nociceptors in the skin, display reduced hypersensitivity and recover more rapidly in response to inflammation [191].

Conclusions

In conclusion, the in vitro and in vivo data on the role of NGF on immune and inflammatory responses are in apparent contradiction. In vitro data suggest that NGF potentiates immune and inflammatory responses (particularly in innate immune cells), leading to the hypothesis that NGF contributes to maintain an “alert” state of the immune system. On the other hand, the marked increase in NGF production in inflammatory conditions (both in humans and animals), and in animal models of inflammatory disease, appears to have an anti-inflammatory, immunosuppressive function. This effect appears to be mediated by a direct action on immune cells (reduced migration and antigen presentation and increased production of IL-10) or indirectly by inducing production of neurotransmitters and neuropeptides. The increase in NGF production at inflammatory sites may, therefore, represent an effort to avoid excessive host inflammation and to restore homeostasis.

We still need to reconcile these in vivo effects with the in vitro data. It is certainly possible that studies based only on in vitro approaches might underestimate the complexity of the interactions of mechanisms operated in vivo by NGF. However, the in vivo data described here were all obtained from animal models of diseases that do not reflect a physiological condition. Since NGF is constitutively produced in all tissues in ‘steady state’ conditions, there is a need for in vivo studies to address the possible role of NGF in immune cells in the absence of inflammation. Taking all the available data together, it is tempting to hypothesize that during normal conditions, NGF might represent one of the signals that keeps the immune system “on guard” but when the immune system is activated and tissue damage occurs, increased NGF may provide a regulatory feed-back signal.  A dual role of NGF depending on the state of the organism might therefore be envisioned. However, the molecular mechanisms and the different mediators involved in these “dual” effects need to be identified. This is of particular relevance in the light of possible pharmacological manipulation of NGF in disease states.

Acknowledgements

The author wishes to thank Dr. Fabrizio de Benedetti and Prof. Maria Egle de Stefano for their suggestions and critical reading of the manuscript. This review is dedicated with friendship and gratitude to Prof. Rita Levi-Montalcini and Prof. Thomas Lundeberg for sharing over the years their physiological and integrative vision of NGF.

Nonstandard Abbreviations: APC, Antigen presenting cells; BBB, Endothelial brain-blood barrier; CGRP, Calcitonin Gene-Related Peptide; CHS, Contact hypersensitivity responses; CIPA, Congenital insensitivity to pain with anhidrosis; CNS, Central nervous system; COX2, Cyclooxygenase2; DRG, Dorsal root ganglia; EAE, Experimental autoimmune encephalomyelitis; IL-1beta, Interleukin-1 beta; LPS, Lipopolysaccharide; MBP, Myelin basic protein; NPY, Neuropeptide Y; SLE, Systemic Lupus Erythematosus; SP, Substance P; TH, Tyrosine hydroxylase; TNCB, Trinitrochlorobenzene; TNF-alpha, Tumor necrosis factor; UVB, Ultraviolet B irradiation

Author(s) Affiliation

L Bracci-Laudiero – Institute of Neurobiology and Molecular Medicine, CNR, 00143 Rome, and Children’s Hospital Bambino Gesù IRCCS Research Laboratories, Department of Immunology, 00165 Rome, Italy

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