Cytokines and peripheral nerve disorders

ARTICLE

Peripheral nervous system (PNS) disorders include all diseases affecting cell bodies of peripheral neurons (e.g. sensory neurons in dorsal root ganglia) or peripheral nerves at the root, plexus, or truncal level. Peripheral nerve disorders may be either focal or diffuse, and are classified using clinical, electrophysiological and histopathological criteria into one of the following categories: neuronopathy (primary involvement of the cell body), axonopathy (primary involvement of the axon, usually length-dependent), or demyelinative neuropathy (primary involvement of the myelin sheath, usually characterized by segmental demyelination). A wide range of traumatic or compressive, hereditary, toxic, dysmetabolic, infectious, and dysimmune processes may be associated with or present as peripheral neuropathies.

Cytokines and growth factors may be produced in and by peripheral nerve tissue during physiological and pathological processes in animals. The role of proinflammatory and antiinflammatory cytokines in the pathogenesis of inflammatory demyelinative neuropathies has been recently investigated in humans.

SOURCES OF CYTOKINES IN PNS

Macrophages are considered to be important sources of cytokines in the PNS. Normal peripheral nerves house resident macrophages (for review [1]). Similarly to resident macrophages in other tissues, they derive from bone marrow stem cells under the influence of macrophage colony-stimulating factor (M-CSF). They account for 2-9% of all endoneurial cells, and are found around blood vessels, among nerve fibers in the endoneurium, and around sensory neuron cell bodies. They probably represent the primary antigen-presenting cells of the PNS. Recruited macrophages represent the other population of macrophages observed in nerves. They derive from monocytes that transmigrate from blood to nerve during demyelination or axonal degeneration. Following transmigration of macrophages, fine targeting to the lesion and phagocytosis of myelin or myelino-axonal debris occur. A key event in the sequence of macrophage activation is the expression of MHC class II antigens. In inflammatory disorders, interferon-gamma (IFN-gamma), derived from lymphocytes, probably represents the major stimulus for class II expression. However, MHC class II expression is also a prominent feature of Wallerian degeneration, in which lymphocytes are not recruited into nerves [2]. The factors involved in macrophage activation during Wallerian degeneration are unknown, but presumably derive from neural cells. Macrophage-derived cytokines most relevant to the PNS include the multifunctional cytokines IL-1 and TNF-alpha (that stimulate transcription of the IL-6 gene in macrophages, fibroblasts and endothelial cells), IL-12 that directs the immune response toward the T1 type (favoring the production of IFN-gamma and IL-2), and IL-15 that stimulates proliferation of T lymphocytes. Macrophage deactivating factors mainly include TGF-ß1 and IL-10.

Another likely important source of cytokines in nerves are mast cells which differentiate in bone marrow under the influence of the kit ligand/c-kit system [3]. They are uncommon in the normal human nerve but can be abundant around microvessels in peripheral neuropathies, especially in demyelinative neuropathies [4]. Mast cells promptly degranulate at the time of axotomy, in vivo, and after exposure to purified myelin, in vitro [5]. Mast cells are the main source of histamine, and they release many preformed cytokines, such as TNF-alpha, IL-4 and IL-10, ß-chemokines and other biologically active molecules [6]. The contribution of mast cell-derived cytokines in PNS disease has not been explored. It is likely, however, that they are crucially involved in blood nerve barrier breakdown and subsequent endoneural edema [7], initiation of leukocyte infiltration [6], myelin breakdown [5], and angiogenesis [8].

Endothelial cells are an important target, if not an important source, of cytokines. Blood-nerve barrier breakdown is an early and key event in immune-mediated peripheral neuropathies. Endothelial cells are activated by molecules derived from mast cells, macrophages, and lymphocytes, such as IFN-gamma, TNF-alpha, and IL-1 [9]. Activated endothelial cells express MHC class II antigens and become antigen presenting cells. Activation is associated with increased vascular permeability for soluble macromolecules. IL-8 production and expression of ICAM-1 and VCAM-1 on endothelial cells favor lymphocyte attraction and adhesion, a prerequisite for transmigration of leukocytes [10].

Cytokine production by neural cells in PNS (i.e. Schwann cells and neurons) is largely unknown. Schwann cells can express MHC class II antigens in disease [11], and probably represent a minor antigen presenting cell of the PNS [1]. Schwann cells initiate myelin degeneration by sequestering myelin fragments (that form the so-called myelin "ovoids") and begin myelin degradation (review in [12]). Whether Schwann cells subsequently act as phagocytes of myelin debris, similarly to macrophages [13], is debated [12]. Schwann cells, however, may express macrophage-associated antigens, such as KP1 (CD68) and Ki-M1P, in disease [14]. IL-1 has been detected in Schwann cells, in vitro [15], and in both myelinating and non-myelinating Schwann cells, in disease [16, 17]. Schwann cells are the major source of ciliary neurotrophic factor (CNTF) [18] and can produce leukemia inhibitory factor (LIF) and IL-6 [19], the 3 molecules forming the family of neuropoietins [20]. These neurotrophic factors are related on the basis of their predicted structural similarities, the fact that they share a common receptor component, the gp130 signal transducing subunit, and that they act on cells via the same signaling pathway. Schwann cells are also able to produce TGF-ß, including TGF-ß2 and ß3 [21], and, in one report, TGF-ß1 [22]. They also produce IL-10 mRNA, another immunosuppressive cytokine, which is detected in some Schwann cells of the normal rat sciatic nerve [23]. Some reports have mentioned positive immunoreactivities for some cytokines in neurons of the central nervous system [20], but very little is known about neuronal production of cytokines in PNS. Positive IFN-gamma immunoreactivity was reported in peripheral sensory and motor neurons, but it was shown to correspond to a structural neuronal protein different from IFN-gamma [24]. IL-1alpha immunoreactivity was detected in peripheral neurons [20], and TGF-ß2 and ß3 were detected in sensory ganglia and axons in rats [21]. An additional source of cytokines in the PNS may be endoneural fibroblasts, that have been shown to produce IL-6 mRNA [25].

CYTOKINES IN NERVE DEGENERATION/
REGENERATION FOLLOWING AXOTOMY

Circulating IL-6 levels transiently peak within 24 hours after nerve crush in rats, TNF-alpha and IL-1 levels peak from day 8 to day 13, and IL-2 levels progressively increase from day 10 to day 18 and then progressively decrease [26]. It is most likely that these cytokines are released from the transected nerve. TNF-alpha is slightly expressed in transected nerves [27]. IL-6 and LIF mRNAs are strongly upregulated in both proximal and distal nerve stumps a few hours after nerve transection [19, 25, 28]. TGF-ß1 mRNA is also highly upregulated at the wound site, 6 hours after nerve injury in mice [29]. Subsequently, IL-6, LIF and TGF-ß1 mRNAs remain overexpressed for several weeks in the proximal nerve stump, the denervated distal fragment, or both [19, 28, 29]. IL10 mRNA is also strongly expressed in Schwann cells from day 2 to day 4 after nerve transection in rats [23].

Axotomy induces Wallerian degeneration, i.e. acute myelinoaxonal degeneration in the distal nerve stump associated with infiltration of scavenger macrophages and Schwann cell proliferation that precedes axonal regrowth [2, 30]. It has been suggested that neurotoxic effects of TNF-alpha may be instrumental in Wallerian degeneration [27]. Indeed, both TNF-alpha and TNF-ß injected into mouse sciatic nerve induce axonal degeneration of up to 80% of the nerve fibers [31, 32]. Interleukin-1 may play several roles in the course of Wallerian degeneration. It acts as a co-mitogen for Schwann cells [33] and up-regulates GM-CSF in endoneural fibroblasts. Granulocyte macrophage-colony stimulating factor stimulates macrophage proliferation and phagocytosis of myelinoaxonal debris by inducing surface expression of the galactose-specific lectin MAC-2 on scavenger cells [34]. As many other cytokines which are overexpressed after axotomy, IL-1 is involved in nerve regeneration. IL-1 may induce production of NGF and other neurotrophic factors, such as LIF, in nerve tissue [20, 35]. The role of IL-1 in neural growth is confirmed by the inhibitory action of IL-1 receptor antagonist (IL-1ra) on axonal regeneration [36]. TGF-ß1 is released by denervated Schwann cells. It acts as a potent mitogen for Schwann cells, which remain non-myelinating during the proliferation stage [37, 38]. It stimulates and synergizes NGF production favouring neural growth [39, 40]. Axonal contact on Schwann cells downregulates TGF-ß1 expression, which allows the begining of myelination [22]. LIF promotes generation and survival of sensory and motor neurons [41, 42] and is transported in a retrograde manner in neurons after peripheral nerve lesion [43]. IL-6 also has neurotrophic effects and acts as a neuronal differentiating factor on PC12 cells [44]. Interestingly, the closely related neurotrophic cytokine CNTF, which is strikingly expressed in normal Schwann cells, is markedly downregulated during Wallerian degeneration in the distal segment, and to a lesser extent in the proximal stump [45]. Expression returns to normal after axon-Schwann cell contact, at the time of myelination of regenerated axon sprouts, suggesting that CNTF represents a neuroprotective molecule preventing neuron cell death [46] rather than a promotor of nerve regeneration.

CYTOKINES AND INFLAMMATORY NEUROPATHIES

Acute inflammatory demyelinative neuropathy, or Guillain-Barré syndrome (GBS), is a rapidly evolving, paralytic illness. Spontaneous recovery usually begins within 2 to 4 weeks after progression of the paralysis ceases. The pathologic feature is widespread inflammatory demyelination of the peripheral nervous system. The autoimmune origin of GBS is supported by the usual exposure to foreign antigens prior to onset, (e.g. vaccination, viral or bacterial infection), circulating antiglycoconjugate antibodies, and activated lymphocytes in blood and in nerve tissue. Demyelination could be mediated by activated lymphocytes and by resident and recruited macrophages [1, 47].

Evaluations of circulating cytokines in affected individuals and experimental allergic neuritis (EAN), the animal model of GBS induced by the injection of peripheral nerve P0 or P2 myelin proteins, have provided arguments for a role of proinflammatory cytokines in the pathogenesis of GBS [47]. IL-2 [48], IL-2 receptor [49, 50] IL-6 [51], and TNF-alpha [52-55] have been found to be elevated in the peripheral blood of patients with GBS. In a recent study, we determined serum levels of TNF-alpha and the specific antagonists soluble TNF-alpha receptors (sTNF-Rs) p55 and p75 in 24 patients with GBS [55]. Increased serum levels of sTNF-Rs were found in almost all patients (96%), and correlated positively with disease severity. Sixty-three percent of patients had increased serum TNF-alpha levels at day 1 of hospitalization. Progression and plateau phases of GBS were associated with elevated serum levels of TNF-alpha and sTNF-Rs, whereas recovery was associated with a decrease of TNF-alpha contrasting with a sustained elevation of sTNF-R p55 serum levels. This study shows that the TNF-alpha system is activated in almost all patients with GBS. The fall in TNF-alpha levels contrasting with the sustained elevation of sTNF-R p55 during recovery of GBS suggests that sTNF-R p55 may be important in the fading of the TNF-alpha-associated neural inflammation [55].

In EAN, macrophages showing positive immunoreactivity for TNF-alpha appear in nerve tissue during the first clinical symptoms and disappear during recovery [27]. TNF-alpha and TNF-ß are implicated in the early breakdown of the blood nerve barrier through upregulation of endothelial adhesion molecules [32, 47]. Injection of TNF-alpha into the nerve leads to neural inflammation, within 3 days, and conspicuous demyelination within 6-7 days after injection [32]. Anti-TNF-alpha antibodies decrease autoimmune inflammatory demyelination in both central and peripheral nervous system [27, 56].

The severity of EAN is increased by systemic administration of recombinant IFN-gamma, and monoclonal antibody to IFN-gamma can suppress EAN [57].

Spontaneous recovery from GBS suggests an important role for the modulation of the biological activity of proinflammatory cytokines. We recently investigated the possible role of TGF-ß1, a molecule that antagonizes the effects of TNF-alpha, IL-1, IL-2, and IFN-gamma and which behaves as a potent anti-inflammatory cytokine [58-59]. We designed a study that evaluated circulating levels TGF-ß1 from the progressive phase to late recovery of paralysis, in a total number of 39 GBS patients [60]. Plasma TGF-ß1 levels were low on admission, further decreased during the progressive phase, and then stabilized and progressively increased up to control levels by the time of early recovery. Circulating TGF-ß1 levels further increased until late recovery. TGF-ß1 plasma levels correlated positively with motor function, the lowest values being observed in the most disabled patients. Other cytokines were randomly elevated (IL-2, IL-6), or remained undetectable in the circulation (IL-1, IL-4, IL-7, IL-10) [60]. It seems likely that downregulation of TGF-ß1 observed at the time of progression of the paralysis participates in the inflammatory process of GBS. Indeed, suppressed TGF-ß1 production in knockout mice is associated with severe tissue inflammation [61-62]. Upregulation of TGF-ß1 during recovery is consistent with the role ascribed to TGF-ß1 in both immunosupression and tissue repair [63]. In EAN, TGF-ß1 mRNA levels peak in nerves just before the beginning of clinical recovery [64]. Systemic administration of recombinant TGF-ß1 abrogates experimental allergic encephalitis (EAE) [65] and TGF-ß2 attenuates EAN [66]. TGF-ß1 downregulates IFN-gamma-induced MHC class II expression in human cell lines [67], mediates T-cell suppression [68-69], decreases T-cell adhesiveness on endothelial cells [70], and deactivates macrophages by suppressing the production of oxygen species such as superoxide and nitric oxide [71-72], two compounds likely to be involved in demyelination [47].

Chronic inflammatory demyelinating polyneuropathy (CIDP) is commonly considered to be the chronic equivalent of GBS. It is characterized by either a chronic monophasic progression or a remitting and relapsing course of paralysis. Elevated serum levels of IL-2 [48] and cerebrospinal fluid levels of IL-6 [51] have been reported in idiopathic CIDP. However, cytokine expression has been mainly studied in POEMS syndrome, a rare, multisystem disorder usually associated with osteosclerotic myeloma and characterized by the combination of Polyneuropathy (CIDP), Organomegaly (affecting the liver, spleen and lymph nodes), Endocrinopathy (affecting all endocrine functions and manifesting as impotence and gynecomastia), M protein (mainly IgG or IgA with a lambda light chain), skin changes (hyperpigmentation, skin thickening, hypertrichosis), and various other clinical and pathological signs such as cachexia, fever, edema, finger clubbing, angiomas, thrombocytosis and angiofollicular lymph node hyperplasia similar to multicentric Castleman's disease. The pathogenesis of POEMS syndrome remains undetermined. Unlike polyneuropathies associated with IgM gammopathies, an autoimmune mechanism directed toward peripheral nerve components has not been demonstrated in POEMS syndrome. We, and others, have suggested that cytokines which act in synergy on the immune, nervous and endocrine systems, could play a role in the expression of the POEMS syndrome [73-77].

We evaluated circulating levels of proinflammatory cytokines (TNF-alpha, IL-1ß, IL-2, IL-6, IFN-gamma), antiinflammatory cytokines (TGF-ß1, IL-4, IL-10, IL-13), the cytokine carrier protein alpha2 macroglobulin, IL-1ra, sTNF-R p55 and p75, and soluble IL-6 receptor (sIL-6-R), in 15 patients with POEMS syndrome and 15 with multiple myeloma [77]. Patients with POEMS syndrome had higher serum levels of IL-1ß, TNF-alpha, and IL-6 and lower serum levels of TGF-ß1 than patients with multiple myeloma. Serum levels of IL-2, IL-4, IL-10, IL-13, IFN-gamma, alpha2 macroglobulin and sIL-6-R were similar in both groups. IL-1ra and sTNF-Rs were increased in POEMS syndrome, but out of proportion to the increase of IL-1ß and TNF-alpha. Serial evaluations in one patient treated with retinoic acid showed that proinflammatory cytokine serum levels paralleled disease activity as assessed by platelet count, gammopathy, and, to some extent, neurologic involvement [78]. These results support the view that manifestations of POEMS syndrome could result from a marked and protracted activation of the proinflammatory cytokine network (IL-1ß, IL-6 and TNF-alpha) associated with a weak, or even decreased (TGF-ß1), antagonistic reaction insufficient to counteract the noxious effects of the cytokines. Relevance to most manifestations of the disease is striking in light of the biological effects of proinflammatory cytokines in animal studies. Osteosclerosis is one puzzling exception, since IL-1ß, IL-6 and TNF-alpha are well known to induce degradation of bone. For this reason, circulating levels of four osteogenic growth factors (epidermal growth factor: EGF, fibroblast growth factor: FGF, platelet derived growth factor: PDGF, and vascular endothelial growth factor/vascular permeability factor: VEGF/VPF) were determined in 14 patients with POEMS syndrome [79]. Patients with POEMS syndrome had markedly increased circulating levels of VEGF/VPF, as compared to patients with multiple myeloma, confirming a previous report [80] involving monoclonal gammopathy of undetermined significance, and GBS. Other growth factors tested were similar to controls. In addition to osteosclerosis, VEGF/VPF overexpression may be relevant to the pathogenesis of other manifestations of the disease, including the neuropathy. CIDP in POEMS syndrome is characterized by the presence of endoneural edema and uncompacted myelin lamellae and, therefore, has long been consisered as possibly related to an increased pressure in the endoneural space [81-82]. Indeed, the main target of VEGF/VPF is the endothelial cell. VEGF/VPF induces a rapid and reversible increase of vascular permeability at very low concentrations, and represents the most potent molecule acting as a vascular permeability factor described to date. Vascular effects of VEGF may be implicated in many other manifestations of POEMS syndrome, such as peripheral edema, anasarca, papillar edema, aqueous diarrhea, angiomas, and arteriopathy [83]. The sources of proinflammatory cytokines and VEGF/VPF in POEMS syndrome remain largely unknown. One possibility is that the plasma cell clones itself produce these molecules. Another possibility is that non-tumor cells, such as stromal cells in bone marrow or cells throughout the body, are activated by the gammopathy or its lambda light chain to produce cytokines. Consistent with the second hypothesis, we detected IL-1mRNA-producing cells in lymph nodes without evidence of monoclonal plasma cell infiltration [76], and both IL-1 mRNA-producing cells and VEGF/VPF-expressing cells around, but not within, myeloma cell aggregates in bone marrow biopsies of patients with POEMS syndrome (Gherardi et al., unpublished data).

CONCLUSION

We believe that cytokines such as IL-1ß and IL-6, that are able to stimulate production of VEGF/VPF, probably integrate their own effects with those of VEGF/VPF to induce most systemic manifestations of POEMS syndrome [79]. These molecules probably represent a link to the plasma cell tumor, removal of which is associated with complete recovery from the syndrome [84], and from expression of the disease.

Acknowledgments.

This study was supported by a Projet Hospitalier de Recherche Clinique (AP/HP), the Collège des Enseignants de Neurologie, and the Institut Garches.

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