Evelin Hagen

Stress Inhibits Hair Growth in Mice by Induction of Premature Catagen Development and Deleterious Perifollicular Inflammatory Events via Neuropeptide Substance P-Dependent Pathways

It has been much disputed whether or not stress can cause hair loss (telogen effluvium) in a clinically relevant manner. Despite the paramount psychosocial importance of hair in human society, this central, yet enigmatic and controversial problem of clinically applied stress research has not been systematically studied in appropriate animal models. We now show that psychoemotional stress indeed alters actual hair follicle (HF) cycling in vivo, ie, prematurely terminates the normal duration of active hair growth (anagen) in mice. Further, inflammatory events deleterious to the HF are present in the HF environment of stressed mice (perifollicular macrophage cluster, excessive mast cell activation). This provides the first solid pathophysiological mechanism for how stress may actually cause telogen effluvium, ie, by hair cycle manipulation and neuroimmunological events that combine to terminate anagen. Furthermore, we show that most of these hair growth-inhibitory effects of stress can be reproduced by the proteotypic stress-related neuropeptide substance P in nonstressed mice, and can be counteracted effectively by co-administration of a specific substance P receptor antagonist in stressed mice. This offers the first convincing rationale how stress-induced hair loss in men may be pharmacologically managed effectively.

Indications for a ‘brain–hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P

It has long been suspected that stress can cause hair loss, although convincing evidence of this has been unavailable. Here, we show that in mice sonic stress significantly increased the number of hair follicles containing apoptotic cells and inhibited intrafollicular keratinocyte proliferation in situ. Sonic stress also significantly increased the number of activated perifollicular macrophage clusters and the number of degranulated mast cells, whereas it down‐regulated the number of intraepithelial γδ T lymphocytes. These stress‐induced immune changes could be mimicked by injection of the neuropeptide substance P in nonstressed mice and were abrogated by a selective substance P receptor antagonist in stressed mice. We conclude that stress can indeed inhibit hair growth in vivo, probably via a substance P‐dependent activation of macrophages and/or mast cells in the context of a brain‐hair follicle axis.

A new role for neurotrophins: involvement of brain-derived neurotrophic factor and neurotrophin-4 in hair cycle control

Neurotrophins exert many biological effects not directly targeted at neurons, including modulation of keratinocyte proliferation and apo‐ptosis in vitro. Here we exploit the cyclic growth and regression activity of the murine hair follicle to explore potential nonneuronal functions of neurotrophins in the skin, and analyze the follicular expression and hair growth‐modulatory function of BDNF, NT‐4, and their high‐affinity receptor, TrkB. The cutaneous expression of BDNF and NT‐4 mRNA was strikingly hair cycle dependent and peaked during the spontaneous, apoptosis‐driven hair follicle regression (catagen). During catagen, BDNF mRNA and immunoreactivity, as well as NT‐4‐immunoreactivity, were expressed in the regressing hair follicle compartments, whereas TrkB mRNA and immunoreactivity were seen in dermal papilla fibroblasts, epithelial strand, and hair germ. BDNF or NT‐4 knockout mice showed significant catagen retardation, whereas BDNF‐overexpressing mice displayed acceleration of catagen and significant shortening of hair length. Finally, BDNF and NT‐4 accelerated catagen development in murine skin organ culture. Together, our data suggest that BDNF and NT‐4 play a previously unrecognized role in skin physiology as agents of hair growth control. Thus, TrkB agonists and antagonists deserve exploration as novel hair growth‐modulatory drugs for the management of common hair growth disorders.—Botch‐karev, V. A., Botchkareva, N. V., Welker, P., Metz, M., Lewin, G. R., Subramaniam, A., Bulfone‐Paus, S., Hagen, E., Braun, A., Lommatzsch, M., Renz, H., Paus, R. A new role for neurotrophins: involvement of brain‐derived neurotrophic factor and neurotro‐phin‐4 in hair cycle control. FASEB J. 13, 395–410 (1999)

Heme oxygenases in pregnancy II: HO-2 is downregulated in human pathologic pregnancies.

Problem:  We previously reported a diminished expression of the heme‐degrading enzymes heme oxygenases (HO)‐1 and HO‐2 in decidua and placenta from mice undergoing Th1‐mediated abortion, strongly indicating the protective effect of HO in murine pregnancy maintenance. Here we investigated whether the expression of HO‐1 and HO‐2 is also reduced at the feto‐maternal interface of pathologic human pregnancies.

Intercellular Adhesion Molecule-1/LFA-1 Cross Talk Is a Proximate Mediator Capable of Disrupting Immune Integration and Tolerance Mechanism at the Feto-Maternal Interface in Murine Pregnancies

Our understanding why a woman’s immune system does not reject her histoincompatible fetus is still very limited. Distinct insights into the mechanisms involved in pregnancy maintenance may help us to prevent pregnancy complications, e.g., miscarriages or pre-eclampsia. Immune integration and tolerance at the feto-maternal interface appear to be indispensable for successful pregnancy maintenance. Little is known about the cross talk between ICAM-1, expressed on epithelium, endothelium, and APC, and its ligand, LFA-1, at the feto-maternal interface. However, based on the role of ICAM-1/LFA-1 in allograft acceptance or rejection upon transplantation, adhesion molecules are likely to interfere with successful pregnancy outcome. In this study, we tested the hypothesis that ICAM-1/LFA-1 pathways may be involved in pregnancy rejection in murine models. By blocking ICAM-1/LFA-1-mediated intercellular adhesion events, we show that fetal immune acceptance is restored in challenged pregnancies (e.g., upon exposure to sound stress), and adoptive transfer of LFA-1 cells into pregnant mice induces rejection only in abortion-prone mouse models. ICAM-1/LFA-1 cross talk leads to increased recruitment of proinflammatory cells to the implantation site, promotes dendritic cell maturation in the decidua, and subsequently induces additional local Th1 polarization via mature dendritic cells. Furthermore, our observations clearly point out that mechanisms of fetal tolerance, e.g., indoleamine 2,3-dioxygenase expression, presence of CD4+CD25bright regulatory T cells, and synthesis of asymmetric Abs, are ICAM-1/LFA-1 dependent. Hence, our data shed light on a hierarchical network of immune integration at the feto-maternal interface, in which ICAM-1/LFA-1 cross talk is clearly a proximate mediator capable of disrupting successful pregnancy maintenance.

Heme oxygenase is downregulated in stress-triggered and interleukin-12-mediated murine abortion.

Heme oxygenases (HOs) are responsible for heme degradation. Besides their enzymatic activities, HOs are involved in tissue protection. Failing upregulation of HOs has been linked to increased necrosis in inflammatory tissues. Interestingly, previously published data indicated that mice exposed to sonic stress during early gestation show an augmented production of decidual inflammatory T‐helper 1 (Th1) cytokines, thus resulting in increased abortion rate. No data linked the Th1‐inducer interleukin (IL)‐12 with the event of abortion. As little is known about the role of HO in pregnancy maintenance, we evaluated the expression of decidual and placental HO‐1 and HO‐2 in the abortion‐prone murine mating combination CBA/J × DBA/2 J with (1) CBA/J female control mice, (2) CBA/J mice exposed to stress during early gestation and (3) CBA/J females injected with recombinant IL‐12. Decidual and placental HOs protein expression was analysed by immunohistochemistry and mRNA levels by real time polymerase chain reaction (PCR).

Is there a ‘gut–brain–skin axis’?

Please cite this paper as: Is there a ‘gut–brain–skin axis’? Experimental Dermatology 2010; 19: 401–405.

Th1 cytokines and the prothrombinase fgl2 in stress-triggered and inflammatory abortion

PROBLEM:  The immune system contributes to the outcome of pregnancy by complex immunological interactions. Cytokines especially influence the immune milieu pro or contra pregnancy. T helper 1 (Th1) cytokines [tumor necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ)] cause inflammation and together are thought to threaten the maintenance of pregnancy. It has been proposed that increased levels of these Th1 cytokines activate coagulation via up‐regulating the novel prothrombinase, fgl2. This study further investigates the Th1 cytokine up‐regulation of fgl2 expression in a pathophysiological, stress induced abortion model, and an inflammatory, interleukin‐12 (IL‐12) triggered abortion model.

Stress-Induced Neurogenic Inflammation in Murine Skin Skews Dendritic Cells Towards Maturation and Migration : Key Role of Intercellular Adhesion Molecule-1/Leukocyte Function-Associated Antigen Interactions

The skin continuously serves as a biosensor of multiple exogenous stressors and integrates the resulting responses with an individuals central and peripheral endogenous response systems to perceived stress; it also acts to protect against external challenges such as wounding and infection. We have previously shown in mice that stress induces nerve growth factor- and substance P-dependent neurogenic inflammation, which includes the prominent clustering of MHC class II(+) cells. Because the contribution of dendritic cells (DCs) in response to stress is not well understood, we examined the role of DCs in neurogenic inflammation in murine skin using a well-established murine stress model. We show that sound stress increases the number of intradermal langerin(+) and CD11c(+) DCs and induces DC maturation, as indicated by the up-regulated expression of CD11c, MHC class II, and intercellular adhesion molecule-1 (ICAM-1). Blocking of ICAM-1/leukocyte function-associated antigen-1 interactions significantly abrogated the stress-induced numeric increase, maturation, and migration of dermal DCs in vivo and also reduced stress-induced keratinocyte apoptosis and endothelial cell expression of ICAM-1. In conclusion, stress exposure causes a state of immune alertness in the skin. Such adaptation processes may ensure protection from possible infections on wounding by stressors, such as attack by predators. However, present-day stressors have changed and such adaptations appear redundant and may overrun skin homeostasis by inducing immune dermatoses.

Neutralization of LPS or blockage of TLR4 signaling prevents stress-triggered fetal loss in murine pregnancy

Maternal stress can cause loss of both histocompatible (syngeneic) and histoincompatible (semiallogeneic) embryos in pregnant mice. Stress increases abortogenic Th1 cytokines and reduces levels of anti-abortogenic Th2 cytokines, progesterone levels, and T regulatory cell activity. While physiological levels of interferon-γ promote vascular remodeling at the feto-maternal interface, an overshooting Th1 cytokine response requires a Toll-like receptor (TLR)-mediated “danger signal” such as lipopolysaccharide (LPS). Interestingly, stress can enhance permeability of mucosal membranes to entry of bacterial products and promote transmucosal migration of commensal bacteria. We hypothesized that bacterial component such as LPS may provide the danger signal through which stress triggers maternal immune activation, subsequently resulting in fetal rejection. Blocking the TLR4 receptor for LPS or neutralization of LPS using bactericidal permeability increasing protein abrogate fetal loss due to sonic stress challenge in DBA/2J-mated CBA/J mice. These treatments prevented stress-triggered immune responses in the decidua, upregulated Treg cells, and reduced the frequency of mature dendritic cells in uterine-draining lymph nodes but not in the uterus. Interestingly, anti-TLR4 treatment only partly ameliorated stress-induced endocrine responses, such as increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression but not decrease of serum progesterone. Galectin-1 knock-out mice were more susceptible to stress-triggered complete implantation failure rather than fetal loss, which was also abolished by LPS neutralization. Insights provided in this paper shed new light on the mechanisms by which stress affects pregnancy outcome and introduce microbial-derived LPS as a mediator within the cascade of stress-triggered immune and endocrine events during pregnancy.