Original Article

Journal of Investigative Dermatology Symposium Proceedings (2003) 8, 195–198; doi:10.1046/j.1087-0024.2003.00808.x

Neurotrophins and Their Role in Pathogenesis of Alopecia Areata

Vladimir A Botchkarev

Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA

Correspondence: Vladimir A. Botchkarev, Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA, 02112, USA; Email: vladbotc@bu.edu

Received 21 January 2003; Revised 21 January 2003; Accepted 21 January 2003.

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Abstract

Neurotrophins comprise a family of structurally and functionally related proteins that are critical for the development and maintenance of cutaneous innervation. They also fulfill multiple non-neurotrophic functions in skin, including regulation of epidermal proliferation and apoptosis, control of hair follicle development and cycling, and melanogenesis. Numerous indications suggest that neurotrophins play an important role in the pathogenesis of a variety of autoimmune diseases. In this review, we focus on the role of neurotrophins in the pathogenesis of alopecia areata, an autoimmune disorder that affects actively growing hair follicles. Recent data suggest that neurotrophins and their receptors are differentially expressed among the subsets of immune cells in alopecia areata-affected skin. Experimental data suggest that neurotrophins may regulate both the cyclic activity of the hair follicle and the functions of immune cells of inflammatory infiltrates. Additional research is required to bridge the gap between our current knowledge of neurotrophin functions in skin affected by alopecia areata and our knowledge of their potential clinical applications. Progress in this area of research will hopefully lead to the development of multiple applications for neurotrophins and their agonists/antagonists in alopecia areata and other hair growth disorders.

Keywords:

nerve growth factor, autoimmune disorder, apoptosis

Abbreviations:

AA, alopecia areata; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; NT-3, neurotrophin-3; NT-4, neurotrophin-4; p75NTR, p75 low-affinity neurotrophin receptor; TrkA,B,C, tyrosine kinase A, B, C (high-affinity neurotrophin receptors)

Alopecia areata (AA) is an autoimmune disease of actively growing hair follicles that affects about 2% of new patients attending dermatology clinics in the United States and Britain (Price, 1991;Shapiro and Price, 1998). Histologically, it is characterized by peribulbar inflammatory infiltrate of predominantly CD4+ and CD8+ T lymphocytes, macrophages, and Langerhans cells that target follicular keratinocytes, melanocytes, dermal papilla fibroblasts, and endothelial cells (McDonagh and Messenger, 1996;Shapiro and Price, 1998). It has been shown that in AA aberrant expression of HLA class I and II antigens occurs in keratinocytes of the proximal hair follicle epithelium (Messenger et al, 1985;Konig et al, 1997). This abnormal expression leads to autoimmune attack by CD4+ T lymphocytes followed by development of inflammatory cell infiltration composed of CD4+ and CD8+ cells, macrophages, and Langerhans cells (Gilhar et al, 1998;Hoffmann, 1999). AA-affected skin also shows increased proinflammatory TH1 and TH2 cytokines and upregulation of CD28 and CD40L and their ligands (McElwee et al, 2002).

Proinflammatory cytokines such as TNF-alpha, IL-1beta, and IFN-gamma stimulate aberrant expression of ICAM-1 and MHC class II molecules on other hair matrix keratinocytes and dermal papilla fibroblasts (Messenger et al, 1985;Nickoloff and Griffiths, 1991;Tobin et al, 1991;van Baar et al, 1992;Konig et al, 1997). In contrast, AA-resistant mice show upregulation of the counter-regulatory molecules IL-4 and IL-10 (McElwee et al, 2002). Proinflammatory cytokines lead to decrements in growth factor secretion by dermal papilla fibroblasts and result in premature catagen development (Hoffmann, 1999), which is characterized by abnormal patterns of cell degeneration and apoptosis (Tobin et al, 1991;Tobin, 1997). Dermal papilla fibroblasts of AA-affected hair follicles are also characterized by high susceptibility to apoptotic cell death in cell culture (Norris et al, 1995).

There are several indications in the literature suggesting that severe psycho-emotional stress may cause the onset of AA (Thies, 1960;Hordinsky and Ericson, 1996). Immunofluorescence studies suggest that AA is characterized by profound changes in hair follicles and skin innervation (Hordinsky et al, 1999;Hordinsky and Ericson, 1996). Sensory neuropeptides and neurotransmitters released by sensory and autonomic nerve fibers that innervate the skin can directly modulate hair cycle as well as immune cell function (reviewed inAnsel et al, 1997;Paus et al, 1997;Scholzen et al, 1998).

The maintenance and functions of sensory and autonomic nerves in postnatal skin are regulated by locally produced neurotrophic factors that belong to different growth factor families (neurotrophins and TGF-beta/bone morphogenetic proteins; reviewed inLewin and Barde, 1996;Bibel et al, 2000). In this review, we focus on the neurotrophins and show their importance for AA pathogenesis. Specifically, we review the recent data illustrating a previously undiscovered role for neurotrophins in the control of CD8 cell apoptosis in this disease.

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Neurotrophins, their receptors, and the control of cell survival or death

The neurotrophin family consists of four proteins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). All four exert their biological effects as dimers interacting with specific receptors (for review seeBothwell, 1995;Bothwell, 1997). High-affinity receptors for neurotrophins belong to the tyrosine kinase family: TrkA is a high-affinity receptor for NGF, TrkB is a high-affinity receptor for BDNF and NT-4, and TrkC is a high-affinity receptor for NT-3 (Figure 1).

Figure 1.
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Ligand-receptor interactions in the neurotrophin family.

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The four neurotrophin proteins also bind to the p75 kDa neurotrophin receptor (p75NTR), which is a member of the TNF family of receptors containing the cytoplasmic "death" domain involved in mediating apoptosis (for review seeChao et al, 1998;Miller and Kaplan, 2001). p75NTR signaling can mediate apoptosis only when Trk signaling is inactive or suboptimally activated, whereas Trk activation can silence p75NTR apoptotic signaling. It was recently shown that activation of p75NTR signaling by neurotrophins recruits a variety of intracellular adaptor molecules (reviewed inBibel et al, 2000;Miller and Kaplan, 2001; Figure 2). In particular, it was demonstrated in several models that the JNK-p53-Bax pathway is involved in neurotrophin-induced apoptosis (Aloyz et al, 1998;Bamji et al, 1998). The JNK family of stress-activated kinases has been shown to be downstream of p75NTR whereas MKK4/7 and Ask1 kinases act upstream of JNK in p75NTR-mediated apoptosis (Miller and Kaplan, 2001). Activation of the JNK pathway leads to upregulation of p53 protein and to an increase in transcription of p53 target genes, including Bax (Miller and Kaplan, 2001). This results in activation of cellular caspases, DNA fragmentation, and cell death.

Figure 2.
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Apoptotic signaling cascade activated by neurotrophins after binding to p75NTR.

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Neurotrophins and the control of hair growth cycle in normal skin

It is now well appreciated that, besides their involvement in the control of neuronal development, neurotrophins fulfill multiple non-neurotrophic functions and regulate cell proliferation, differentiation, apoptosis, and tissue remodeling outside of the nervous system (reviewed inAloe et al, 1997;Pincelli and Yaar, 1997). Neurotrophins are intimately involved in the control of epidermal homeostasis, and NGF stimulates keratinocyte proliferation and supresses apoptosis in keratinocytes and melanocytes in vitro (reviewed inPincelli, 1997). NGF also stimulates TrkA phosphorylation in keratinocytes and Trk-inhibitor alkaloid K252a suppresses NGF-induced keratinocyte proliferation (Pincelli et al, 1997). As was shown in transgenic and knockout models, BDNF, NT-3, and NT-4 also stimulate keratinocyte proliferation in murine epidermis (Botchkarev et al, 1999b).

We showed that neurotrophins play an important role in the control of hair follicle cycling in normal C57BL/6 mice. During the murine hair cycle, steady-state levels of NGF and NT-3 proteins significantly fluctuate in a hair cycle-dependent manner: NGF levels rose dramatically in early-anagen skin (Welker et al, 1996), but NT-3 was significantly upregulated during catagen (Botchkarev et al, 1998). The steady-state levels of NT-3, BDNF, and NT-4 mRNAs were also significantly increased prior to and during catagen onset (Botchkarev et al, 1998;Botchkarev et al, 1999a). We further showed that neonatal transgenic mice that overexpress NGF, NT-3, or BDNF display accelerated catagen development, and that BDNF-overexpressing mice display a significant shortening of hair length compared to corresponding age-matched wild-type animals (Botchkarev et al, 1998;Botchkarev et al, 1999a; Botchkarev et al, 2000). Conversely, neurotrophin (NT-3, BDNF, and NT-4) null mutants show catagen retardation.

The addition of NT-3, NT-4, and BDNF in vitro significantly stimulates catagen development in C57BL/6 murine skin organ cultures, whereas the p75NTR antagonist cyclic decapeptide abrogates the catagen-stimulatory effects of neurotrophins and retards catagen in situ (Botchkarev et al, 1999a;Botchkarev et al, 1998;Botchkarev et al, 2003). By using p75NTR knockout mice, we showed that the catagen stimulatory effects of neurotrophins are mediated by their binding via p75NTR expressed in keratinocytes of the regressing outer root sheath (Botchkarev et al, 2000a).

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Neurotrophins in pathogenesis of autoimmune disorders

There are numerous indications that neurotrophins play an important role in the pathogenesis of autoimmune diseases (cf.Aloe and Tuveri, 1997;Aloe et al, 1997). A significant increase in basal NGF levels was found in the synovium of patients affected by rheumatoid arthritis, in the cerebrospinal fluid of patients with multiple sclerosis, in the plasma of patients affected by lupus erythematosus, and in the skin of patients with systemic scleroderma (Aloe et al, 1992;Bracci-Laudiero et al, 1992;Bracci Laudiero et al, 1993;Tuveri et al, 1993). Human CD4+ lymphocytes (both TH1 and TH2 subclones) secrete a biologically active form of NGF (Lambiase et al, 1997), and an increase in NGF immunoreactivity was found in experimentally induced inflammatory cell infiltrates in the lungs (Braun et al, 1998). Upregulation of neurotrophins and their receptors was also shown during inflammation in many experimental models (Donovan et al, 1995;Wakabayashi et al, 1996;Dmitrieva et al, 1997), and production of BDNF was recently demonstrated in activated human T cells, B cells, and monocytes (Kerschensteiner et al, 1999).

Increasingly the data suggest that NGF plays a suppressive role in the development of autoimmune response (Ransohoff and Trebst, 2000). It was recently shown that administration of NGF-neutralizing antibodies exacerbates neuropathological signs of experimentally induced autoimmune encephalomyelitis (Micera et al, 2000). Conversely, mice treated with NGF by i.p. injections following induction of experimental autoimmune encephalomyelitis showed a delayed onset of disease and lower clinical scores during the course of disease (Arredondo et al, 2001). Most important, a protective role for NGF against autoimmune encephalomyelitis is achieved via downregulating the production of INF-gamma and upregulating the production of IL-10—that is, via switching the balance of T helper cell type 1 and type 2 cytokines (Villoslada et al, 2000). Taken together, these data suggest that neurotrophins may be important in protecting against autoimmune disorders and in suppressing immune response via downregulation of proinflammatory cytokines and upregulation of TH2 cytokines.

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Neurotrophins in pathogenesis of alopecia areata

We recently showed that, in C3H/HeJ mouse models for AA, cutaneous steady-state levels of neurotrophins determined by ELISA remain as high as those seen in the control nonaffected skin AA (Botchkarev et al, 2000b). This is consistent with previous reports that showed high levels of neurotrophins in other tissues affected by autoimmune disorders (Aloe et al, 1992;Bracci-Laudiero et al, 1992;Bracci Laudiero et al, 1993;Tuveri et al, 1993). In C3H/HeJ mouse back skin, anagen hair follicles not affected by AA showed moderate expression of NGF, absence of BDNF, and coexpression of Trk and p75NTR in the outer root sheath. In the AA-affected anagen hair follicles, the levels of NGF and BDNF were elevated in the outer and inner root sheath, respectively, and all Trk receptors were downregulated in the outer root sheath. In contrast, the apoptotic receptor p75NTR was upregulated in the outer root sheath and was ectopically expressed in the dermal papilla (Palkina et al, 2002).

We showed that neurotrophins were strongly expressed in macrophages in the inflammatory cell infiltrates around the hair follicles. In the AA-affected skin, numerous macrophages, identified by MOMA-2 immunoreactivity, coexpressed TrkB, while dermal dendritic NLDC145-immunoreactive cells were also p75NTR-positive. Double immunolabeling showed that CD8+ cells in the inflammatory infiltrates also expressed p75NTR, implicating involvement of neurotrophins in the control of apoptosis in CD8+ lymphocytes (Palkina et al, 2002).

The latter data were confirmed by FACS analysis showing that 45%–75% of CD8 cells isolated from the affected skin expressed p75NTR whereas no p75NTR was seen on CD4 cells and macrophages (Palkina et al, 2002). NGF or BDNF administration into AA-affected skin was associated with a reduction (p<0.01) in the number of CD8 cells, which coexpressed p75NTR and TUNEL. Conversely, treatment of AA-affected mice with a cyclic peptide that blocks signaling through p75NTR prominently increased the number of CD8 cells in the skin. These data suggest a previously unrecognized role for neurotrophins in stimulating CD8 cell apoptosis in skin affected by AA, and they raise a possibility of exploring stimulators of neurotrophin signaling through p75NTR for the treatment of autoimmune hair loss.

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Conclusions

During the last decade, tremendous progress has been achieved in delineating the molecular structure and function of neurotrophins and their receptors. Although initially identified as growth factors stimulating the development of the nervous system, neurotrophins are now recognized as powerful regulators of tissue remodeling and homeostasis. In normal skin, they are important factors controlling innervation, hair follicle growth, epidermal proliferation, and melanogenesis. Our recent data demonstrate that, in AA-affected skin, neurotrophins may play multiple roles and are involved not only in hair cycle regulation but also in the modulation functions of immune cells (Figure 3). Specifically, they may be closely involved in the control of CD8 lymphocyte numbers via stimulating apoptosis through p75NTR expressed on these cells.

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Neurotrophin involvement in pathogenesis of AA.

Full figure (14K)

Additional research is required to bridge the gap between our current knowledge of neurotrophin functions in skin and our knowledge of their potential clinical applications. The progress in this area of research will, we hope, lead to the development of multiple uses for neurotrophins and their agonists/antagonists in AA and other hair growth disorders.

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Acknowledgements

Critical reading of this manuscript and support of Dr B.A. Gilchrest and Dr M. Yaar are gratefully acknowledged. This work was supported by the grants from the National Alopecia Areata Foundation to V.A.B.

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