Nuove prospettive nell’interpretazione della patogenesi dell’MCS/EHS: una disregolazione dei fattorineurotrofici?

Nuove prospettive nell’interpretazione della patogenesi dell’MCS/EHS: una disregolazione dei fattorineurotrofici?

Ciliary neurotrophic factor (CNTF) is a unique member of the interleukin-6 (IL-6) family, whose receptor subunit for ligand binding is exclusively expressed in the nervous system and muscle. The role of CNTF in mammalian development remains unknown. We recently reported the specific expression of CNTF in the pineal gland and eyes. CNTF plays an inhibitory role in the development of photoreceptor-like cells in early postnatal rat pineal glands.

Inducers of oxidative stress block ciliary neurotrophic factor

activation of Jak/STAT signaling in neurons

N. Kaur,*,

B. Lu,* R.K. Monroe,* S.M. Ward* and S.W. Halvorsen*

ROS inhibit the

activity of ciliary neurotrophic factor (CNTF) in nerve cells.Treatment with hydrogen peroxide (H2O2) as a generator of

ROS inhibited CNTF-mediated Jak/STAT signaling in all cultured nerve cells tested, including chick ciliary ganglion neurons, chick neural retina, HMN-1 motor neuron hybrid cells,

and SH-SY5Y and BE(2)-C human neuroblastoma cells. H2O2

treatment of non-neuronal cells, chick skeletal muscle and

HepG2 hepatoma cells, did not inhibit Jak/STAT signaling

Depleting the intracellular stores of reduced glutathione by

treatment of BE(2)-C cells with nitrofurantoin inhibited CNTF

activity, whereas addition of reduced glutathione protected

cells from the effects of H2O. These results suggest that

disruption of neurotrophic factor signaling by mediators of

oxidative stress may contribute to the neuronal damage

observed in neurodegenerative diseases and significantly affect the utility of CNTF-like factors as therapeutic agents in

preventing nerve cell death. In nerve cells,

unlike other cells, exposure of cells to agents that increase

oxidative stress results in blockade of the Jak/STAT pathway

and disruption of growth factor and cytokine signaling.

CNTF signaling is mediated through activation of the

receptor-associated Janus family of tyrosine kinases, Jak1/

Jak2. Jaks are also activated upon ligand binding to cytokine

receptors such as interferons, growth hormone, prolactin,

leptin, and interleukins, as well as other members of the

CNTF family of neuropoietic cytokines, including leukemia inhibitory factor, cardiotrophin-1, interleukin (IL)-6, IL-11,

cardiotrophin-like cytokine, oncostatin-M and neuropoietin

(Darnell et al. 1994; Elson et al. 1998; Derouet et al. 2004). .

Jak/STAT signaling pathways are

essential for the proper development and maintenance of a

number of tissues. Disrupted or inappropriate signaling can

result in fetal death, developmental disorders, cancers and

inadequate immune responses. The JAK-STAT signalling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through a process called transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors (which bind the chemical signals).[1] Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

Key steps of the JAK-STAT pathway. JAK-STAT signalling is made of three major proteins: cell-surface receptors, Janus kinases (JAKs), and signal transducer and activator of transcription proteins (STATs). Once a ligand (red triangle) binds to the receptor, JAKs add phosphates (red circles) to the receptor. Two STAT proteins then bind to the phosphates, and then the STATs are phosphorylated by JAKs to form a dimer. The dimer enters the nucleus, binds to DNA, and causes transcription of target genes. To move from the cytosol to the nucleus, STAT dimers have to pass through nuclear pore complexes (NPCs), which are protein complexes present along the nuclear envelope that control the flow of substances in and out of the nucleus. To enable STATs to move into the nucleus, an amino acid sequence on STATs, called the nuclear localization signal (NLS), is bound by proteins called importins.[4] Once the STAT dimer (bound to importins) enters the nucleus, a protein called Ran (associated with GTP) binds to the importins, releasing them from the STAT dimer.[6] The STAT dimer is then free in the nucleus. JAK-STAT signalling is able to interconnect with other cell-signalling pathways, such as the PI3K/AKT/mTOR pathway. activating the JAK-STAT pathway can also activate PI3K/AKT/mTOR signalling. JAK-STAT signalling can also integrate with the MAPK/ERK pathway. However, although MAPK can increase transcription induced by STATs, one study indicates that phosphorylation of STAT3 by MAPK can reduce STAT3 activity. One example of JAK-STAT signalling integrating with other pathways is Interleukin-2 (IL-2) receptor signaling in T cells.  the JAK-STAT signalling pathway plays a major role in cytokine receptor signalling. Since cytokines are substances produced by immune cells that can alter the activity of neighbouring cells, the effects of JAK-STAT signalling are often more highly seen in cells of the immune system. For example, JAK3 activation in response to IL-2 is vital for lymphocyte development and function. Also, one study indicates that JAK1 is needed to carry out signalling for receptors of the cytokines IFNγ, IL-2, IL-4 and IL-10.  STAT1 can enable the transcription of genes which inhibit cell division and stimulate inflammation.  STAT4 is able to activate NK cells (natural killer cells), and STAT5 can drive the formation of white blood cells.[2][21] In response to cytokines, such as IL-4, JAK-STAT signalling is also able to stimulate STAT6, which can promote B-cell proliferation, immune cell survival, and the production of an antibody called IgE. JAK-STAT signalling plays an important role in animal development. The pathway can promote blood cell division, as well as differentiation (the process of a cell becoming more specialised).[22] In some flies with faulty JAK genes, too much blood cell division can occur, potentially resulting in leukaemia JAK-STAT signalling has also been associated with excessive white blood cell division in humans and mice. Psoriasis on the hands can be caused by faulty JAK-STAT signalling. Since the JAK-STAT pathway plays a major role in many fundamental processes, such as apoptosis and inflammation, dysfunctional proteins in the pathway may lead to a number of diseases. For example, alterations in JAK-STAT signalling can result in cancer and diseases affecting the immune system, such as severe combined immunodeficiency disorder. Since excessive JAK-STAT signalling is responsible for some cancers and immune disorders, JAK inhibitors have been proposed as drugs for therapy. For instance, to treat some forms of leukaemia, targeting and inhibiting JAKs could eliminate the effects of EPO signalling and perhaps prevent the development of leukaemia. One example of a JAK inhibitor drug is Ruxolitinib, which is used as a JAK2 inhibitor.STAT inhibitors are also being developed, and many of the inhibitors target STAT3. It has been reported that therapies which target STAT3 can improve the survival of patients with cancer. Another drug, called Tofacitinib, has been used for psoriasis and rheumatoid arthritis treatment.

The importance of Jak/STAT

signaling is apparent from analyses of Jak and STAT gene

knockout phenotypes. Jak1-deficient mice die shortly after

birth, have neuronal defects including a lack of response to

CNTF-like cytokines and show increased apoptosis (Rodig

et al. 1998).

The Journal of Neuroscience, June 15, 1997, 17(12):4633–4641

Differential Susceptibility to Neurotoxicity Mediated by

Neurotrophins and Neuronal Nitric Oxide Synthase

Amer F. Samdani,1 Cheryl Newcamp,1 Annelies Resink,1 Fabrizio Facchinetti,1

Brian E. Hoffman,1 Valina L. Dawson,1,2,3 and Ted M. Dawson1,

Besides having a role in neuronal differentiation and survival, neurotrophins can attenuate neuronal cell

death caused by excitotoxins, glucose deprivation, and ischemia

(Shigeno et al., 1991; Davies and Beardsall, 1992; Frim et al.,

1993; Burke et al., 1994; Cheng and Mattson, 1994; Lindholm). 1994; Mattson et al., 1995; Nakao et al., 1995; Anderson et al.,

1996). Despite the abundance of in vitro and in vivo data that

neurotrophins enhance the survival of neurons after neuronal

injury, Choi and collaborators recently provided provocative data

that neurotrophins under certain conditions enhance excitotoxic

insults (Koh et al., 1995).

Neurotoxicity elicited

by glutamate acting via NMDA receptors is mediated, in part,

by excess production of NO by nNOS (Dawson and Snyder,

1994; Dawson and Dawson, 1996). NMDA neurotoxicity in

primary cerebral cortical cultures is prevented by a variety of

NOS inhibitors (V. Dawson et al., 1991, 1993; T. Dawson et al.,

1993, 1995), and cortical cultures from nNOS-deficient

(nNOS 2) mice are resistant to neurotoxicity (Dawson et al.,

1996).

nNOS expression is increased after NGF treatment in PC-12

cells (Hirsch et al., 1993; Peunova and Enikolopov, 1995) and in rat spinal cord after treatment with BDNF, NT-3, and NT-4

(Huber et al., 1995) and basal forebrain cholinergic neurons

(Holtzman et al., 1994, 1996). Because nNOS expression is regulated by neurotrophins, we wondered whether the potentiation of

excitotoxicity by neurotrophins is mediated via increases in nNOS

expression.

neurotrophin enhancement of

NMDA neurotoxicity occurs via increases in nNOS when neurons

are grown on a glial feeder layer, whereas neurotrophins are

neuroprotective when neurons are grown on a Poly-O matrix.

Recent studies suggest that microglia could contribute

to the excitotoxic injury to neurons via an indirect mechanism

probably secondary to neurocytokine interactions and induction

of iNOS (Hewett et al., 1994). Neurons grown on both the glial

layer and Poly-O matrix would have microglia because measures

were not taken to exclude microglia from the culture paradigms;

thus we cannot exclude the possibility that neurotrophin-mediated

enhancement of excitotoxicity is attributable to indirect actions of

microglia. If microglia are contributing to the enhancement of

excitotoxicity, it is unlikely to be via activation of iNOS, because

cultures lacking nNOS fail to exhibit neurotrophin-mediated enhancement of excitotoxic injury. When neurons are grown on a

Poly-O matrix, BDNF pretreatment is neuroprotective, consistent

with numerous previous reports of the protective role of neurotrophins (Mattson et al., 1989, 1995; Fernandez-Sanchez and

Novelli, 1993; Nozaki et al., 1993; Prehn et al., 1993; Burke et al.,

1994; Cheng and Mattson, 1994; Cheng et al., 1994; Lindholm,

1994; Lindvall et al., 1994; Nakao et al., 1995; Anderson et al.,

1996). Thus, the phenotype of neuronal cultures is influenced

markedly by the culture paradigm. When neurons are grown on a

glial layer, they are being exposed to glia that are ;2–3 weeks

older in age, whereas neurons grown on Poly-O matrix are exposed to glia that are at the same developmental time point. It is

likely that neurons and glia signal to each other during development and differentiation and that neurons grown on glial layers do

not receive the proper signaling and may remain in a more

immature fetal-like state. It is likely that glia of different ages

secrete various “factors” that alter the phenotype of the neurons.

Consistent with this notion is our observation that conditioned

media obtained from glial feeder layers can inhibit completely the

nNOS expression of neurons grown on a Poly-O matrix (A.

Samdani, V. L. Dawson and T. M. Dawson, unpublished observations). To our knowledge there is no demonstration that neurotrophins enhance the susceptibility to neuronal injury in in vivo

studies. Thus, neuronal cultures grown on a Poly-O matrix may

represent more accurately the phenotype of the in vivo neuronal

population. Moreover, when neurons are grown on a Poly-O

matrix, the level of nNOS expression more accurately represents

the adult phenotype.

Numerous studies indicate that neurotrophins are neuroprotective after a variety of toxic insults (Burke et al., 1994; Cheng

et al., 1994; Lindholm, 1994; Lindvall et al., 1994; Mattson et

al., 1995; Nakao et al., 1995; Anderson et al., 1996). We

observe similar neuroprotective properties when neurons are

grown on a Poly-O matrix. Pretreatment of cortical cultures

grown on a Poly-O matrix with BDNF reduces both NMDA

neurotoxicity and SNP neurotoxicity. The mechanisms of

neurotrophin-mediated neuroprotection are not known. However, recent studies indicate that neurotrophin treatment may

stabilize intracellular calcium levels as well as prevent apoptotic death programs (Collazo et al., 1992; Barde, 1994; Barbacid,

1995; Levine et al., 1995; Thoenen, 1995; Tazi et al., 1996).

Peptide growth factors may protect against ischemic toxicity in

culture by preventing NO toxicity (Maiese et al., 1993). They

also prevent peroxynitrite-mediated apoptosis (Estevez et al.,

1995). Furthermore, neurotrophins are trophic and may allow neurons to recover from toxic insults (Hefti, 1986; Tuszynski et

al., 1990; Yan et al., 1992; Koliatsos et al., 1993; Widmer et al.,

1993; Friedman et al., 1995).

TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF

Jin H. Nam, Eun S. Park, So-Yoon Won, Yu A. Lee, Kyoung I. Kim, Jae Y. Jeong, Jeong Y. Baek, Eun J. Cho, Minyoung Jin, Young C. Chung … Show moreAuthor Notes

Brain, Volume 138, Issue 12, December 2015, Pages 3610–3622, https://doi.org/10.1093/brain/awv297

transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP+-lesioned or adeno-associated virus α-synuclein rat models of Parkinson’s disease. activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson’s disease.

Ciliary neurotrophic factor (CNTF) has a neuroprotective effect on dopaminergic neurons. Nam et al. report that the capsaicin receptor TRPV1 expressed on astrocytes mediates the production of endogenous CNTF to inhibit degeneration of dopaminergic neurons in two rodent models of Parkinson’s disease.

Modulation of neuroinflammation: Role and therapeutic potential of TRPV1 in the neuro-immune axis

Author links open overlay panelWei-LinKongYuan-YuanPengBi-WenPeng

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https://doi.org/10.1016/j.bbi.2017.03.007Get rights and content

Highlights

TRPV1 has an extensive expression, especially in the central immune cells.

TRPV1 enhanced in the CNS in response to inflammatory challenges.

Up-regulated expression and activity was due to phosphorylate specific sites.

Inflammatory mediators regulate activity, trafficking and expression of TRPV1.

TRPV1 could regulate inflammatory reactions.

Abstract

Transient receptor potential vanilloid type 1 channel (TRPV1), as a ligand-gated non-selective cation channel, has recently been demonstrated to have wide expression in the neuro-immune axis, where its multiple functions occur through regulation of both neuronal and non-neuronal activities. Growing evidence has suggested that TRPV1 is functionally expressed in glial cells, especially in the microglia and astrocytes. Glial cells perform immunological functions in response to pathophysiological challenges through pro-inflammatory or anti-inflammatory cytokines and chemokines in which TRPV1 is involved. Sustaining inflammation might mediate a positive feedback loop of neuroinflammation and exacerbate neurological disorders. Accumulating evidence has suggested that TRPV1 is closely related to immune responses and might be recognized as a molecular switch in the neuroinflammation of a majority of seizures and neurodegenerative diseases. In this review, we evidenced that inflammation modulates the expression and activity of TRPV1 in the central nervous system (CNS) and TRPV1 exerts reciprocal actions over neuroinflammatory processes. Together, the literature supports the hypothesis that TRPV1 may represent potential therapeutic targets in the neuro-immune axis.

PUFA AND NEURODEVELOPMENT

Brain Ciliary Neurotrophic Factor (CNTF) and hypothalamic control of energy homeostasis

Claire-Marie VACHER Odile COUVREUR Elsa BASIRE
Alain AUBOURG Delphine CREPIN Flavien BERTHOU Nicolas VICAIRE Mohammed TAOUIS

Cytokines play an important role in energy-balance regulation. Notably leptin, an adipocyte-secreted cytokine, regulates the activity of hypothalamic neurons that are involved in the modulation of appetite. Leptin decreases appetite and stimulates weight loss in rodents. Unfortunately, numerous forms of obesity in humans seem to be resistant to leptin action. The ciliary neurotrophic factor (CNTF) is a neurocytokine that belongs to the same family as leptin and that was originally characterized as a neurotrophic factor that promotes the survival of a broad spectrum of neuronal cell types and that enhances neurogenesis in adult rodents. It presents the advantage of stimulating weight loss in humans, despite the leptin resistance. It has been found that CNTF shares signaling pathways with leptin and is expressed in the arcuate nucleus (ARC), a key hypothalamic region controlling food intake. Endogenous CNTF may also participate in the control of energy balance. Indeed, its expression in the ARC is inversely correlated to body weight in rats fed a high-sucrose diet. Thus hypothalamic CNTF may act, in some individuals, as a protective factor against weight gain during hypercaloric diet and could account for individual differences in the susceptibility to obesity.

CNTF is a 200-amino acid cytokine that belongs to the IL-6 family. It is expressed in both the peripheral and the central nervous systems by neuronal and glial cells. Originally, CNTF was shown to promote the survival of ciliary ganglion neurons (Barbin et al., 1984; Helfand et al., 1976) and to play a major role in the adult nervous system’s early response to lesions. Today, we know that its spectrum of functions is much broader since it includes the differentiation and/ or survival of a variety of nervous cells such as motor neurons, oligodendro- cytes and astrocytes (Hughes et al., 1988; Mayer et al., 1994; Sendtner et al., 1992). This effect has been attributed to a resensitization of the ARC to leptin due to a CNTF-induced neurogenesis (Kokoeva et al., 2005). The activation of this signaling pathway by CNTF is negatively modulated by the suppressor of cytokine signaling (SOCS) family of proteins (Bjorbaek et al., 1999). Thus, in rodents, CNTF shares signaling cascades with leptin in the ARC.  CNTF could account for individual differences in the susceptibility to obe- sity. Genetic polymorphisms studies corroborate the involvement of endog- enous CNTF in the control of body weight. Indeed, it has been found that a null mutation in CNTF gene is asso- ciated with a significant increase in body mass in humans (Heidema et al., 2010; O’Dell et al., 2002), and that variants in CNTF or CNTFRa gene in humans are associated to lower age at onset of eating disorders (Gratacos et al., 2010).