Rainer H. Straub

Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol

The skin and its major appendages are prominent target organs and potent sources of key players along the classical hypothalamic‐pituitary axis, such as corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and α melanocyte stimulating hormone (α‐MSH), and even express key steroidogenic enzymes. Therefore, it may have established local stress response systems that resemble the hypothalamic‐pituitary‐adrenal (HPA) axis. However, functional evidence that this is indeed the case in normal human skin in situ has still been missing. We show that microdissected, organ‐cultured human scalp hair follicles respond to CRH stimulation by up‐regulating proopiomelanocortin (POMC) transcription and immunoreactivity (IR) for ACTH and α‐MSH, which must have been processed from POMC. CRH, α‐MSH, and ACTH also modulate expression of their cognate receptors (CRH‐R1, MC1‐R, MC2‐R). In addition, the strongest stimulus for adrenal cortisol production, ACTH, also up‐regulates cortisol‐IR in the hair follicles. Isolated human hair follicles secrete substantial levels of cortisol into the culture medium, and this activity is further up‐regulated by CRH. CRH also modulates important functional hair growth parameters in vitro (hair shaft elongation, catagen induction, hair keratinocyte proliferation, melanin production). Finally, human hair follicles display HPA axis‐like regulatory feedback systems, since the glucocorticoid receptor agonist hydrocortisone down‐regulates follicular CRH expression. Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops.

Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis

Methotrexate (MTX) is a folate analogue originally synthesised in the 1940s and designed to inhibit dihydrofolate reductase.1 Reduced folate (tetrahydrofolate) is the proximal single carbon donor in several reactions involved in the de novo synthetic pathways for purine and pyrimidine precursors of DNA and RNA required for cell proliferation. Furthermore, tetrahydrofolate plays a part in a second important biochemical step: the methionine-homocysteine cycle, which is necessary to provide a methyl group for several downstream reactions such as methylation of DNA, RNA proteins, and others. Therefore, MTX has been used extensively for treatment of neoplastic diseases. In 1951 the rationale for the introduction of MTX for the treatment of rheumatoid arthritis (RA) was that it inhibited proliferation of the lymphocytes and other cells responsible for inflammation in the joint.2 No further studies on clinical experience with MTX in RA were published until the early 1980s, when several uncontrolled trials were reported.3-8 Finally, four well designed, blinded, placebo controlled studies published in 1984 and 1985 introduced the use of MTX in the treatment of RA.9-12 The early indications for MTX use in the rheumatic diseases were first reported in a large review in 1984.13 From the considerable experience obtained over the past 15 years, several lines of evidence clearly suggest that MTX does not act simply as a cytotoxic (antiproliferative) agent for the cells responsible for the joint inflammation in RA.14 As a matter of fact, it would be difficult to understand how a drug that diminishes inflammation by preventing proliferation of immune cells might work at effective concentrations for only a very short time and once a week. In addition, the rapid clinical remission and the short term effect on the acute phase reactants, as seen with low dose MTX administration in most patients with …

Norepinephrine, the β-Adrenergic Receptor, and Immunity

Over the past 20 years, a significant effort has been made to define a role for the neuroendocrine system in the regulation of immunity. It was expected that these experimental findings would help to establish a strategy for the development of clinical interventions to either suppress or augment immunological function for disease prevention. However, the translation of these basic experimental findings into clinical interventions has been difficult. Possible explanations for this difficulty are that the findings from human and animal studies do not agree and/or that the results obtained within one species are rarely verified in the other. Our goal in writing this review is to address this issue by summarizing the published findings from human studies and comparing them to published findings from animal studies. Although far from being exhaustive, this review summarizes and discusses at least the past 10 years of findings in which a change in immunity and a change in catecholamine levels and/or stimulation of the β2-adrenergic receptor has been documented.

The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages

Our objective was to investigate sym‐pathetic and sensory nerve fibers in synovial tissue in rheumatoid arthritis (RA) and osteoarthritis (OA) in relation to histological inflammation and synovial cytokine and norepinephrine (NE) secretion. Immu‐nohistochemistry was used to detect nerve fibers and inflammatory parameters. A superfusion technique of synovial tissue pieces was used to investigate cytokine and NE secretion. In RA, we detected 0.2 ± 0.04 tyrosine hydroxylase‐positive (TH‐positive=sympathetic) nerve fibers/mm2 as com‐pared to 4.4 ± 0.8 nerve fibers/mm2 in OA (P<0.001). In RA, there was a negative correlation between the number of TH‐positive nerve fibers and inflammation index (RRank=−0.705, P=0.002) and synovial secretion (RRank=−0.630, P=0.009), which was not found in OA. Substance P‐positive (=sensory) nerve fibers were increased in RA as compared to OA (3.5 ±0.2 vs. 2.3±0.3/mm2, P=0.009). Despite lower numbers of sympathetic nerve fibers in RA than in OA, NE release was similar at baseline (RA vs. OA: 152±36 vs. 106±21 pg/ml, n.s.). Basal synovial NE secretions correlate with the number of TH‐positive CD 163+ synovial macro‐phages (RA: RRank=0.622, P=0.031; OA: RRank= 0.299, n.s.), and synovial macrophages have been shown to produce NE in vitro. Whereas sympathetic innervation is reduced, sensory innervation is in‐creased in the synovium from patients with long‐standing RA when compared to the synovium from OA patients. The differential patterns of innervation are dependent on the severity of the inflammation. However, NE secretion from the synovial tissue is maintained by synovial macrophages. This demon‐strates a loss of the influence of the sympathetic nervous system on the inflammation, accompanied by an up‐regulation of the sensory inputs into the joint, which may contribute to the maintenance of the disease.—Miller, L. E., Jüsten, H.‐P., Schölmerich, J., Straub, R. H. The loss of sympathetic nerve fibers in the synovial tissue of patients with rheumatoid arthritis is accompanied by increased norepinephrine release from synovial macrophages. FASEB J. 14, 2097–2107 (2000)

Involvement of the hypothalamic–pituitary–adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: Viewpoint based on a systemic pathogenetic role

From the compendium presented above, the following statements become evident: 1) Inappropriately low secretion of cortisol in relation to inflammation is a typical feature of the inflammatory disease in patients with RA. 2) The secretion of adrenal androgens is significantly reduced, which is a problem in postmenopausal women and elderly men due to a lack of downstream sex hormones. 3) Serum levels of testosterone are markedly reduced in RA. 4) Sympathetic nerve fibers are markedly reduced in the synovial tissue of patients with RA, whereas proinflammatory sensory fibers (substance P) are present. 5) Substance P serves to continuously sense painful stimuli in the periphery, and the nociceptive input from the inflamed joint shows a large amplification in the spinal cord. This leads to continuous pain with stabilization of the afferent sensory input and continuous release of proinflammatory substance P into the lumen of the joint. From these facts it is obvious that alterations of the systemic antiinflammatory feedback systems contribute significantly to the pathogenesis of RA. Disease therapy directed at these alterations must provide a mechanism to replace the adrenal glands (glucocorticoids), the gonadal glands (androgens), and the sympathetic nervous system (adenosine increase by low-dose MTX, sulfasalazine, and salicylates) in order to integrate their immunosuppressive effects at the local site of synovial inflammation. Although local processes of the adaptive immune system are important in pathogenesis in the acute phase of RA, these mechanisms may be less important during the chronic phase of the disease in the absence of a specific trigger. We believe that a defect of systemic antiinflammatory feedback systems is an important factor in the perpetuation of RA. This review reinforces the belief that combined therapeutic approaches on a neuroendocrine immune basis are of crucial importance in a pathogenetically oriented therapy of RA.

Estrogens and autoimmune diseases

Abstract:  Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune‐suppressors . Several physiological, pathological, and therapeutic conditions may change the serum estrogen milieu and/or peripheral conversion rate, including the menstrual cycle, pregnancy, postpartum period, menopause, being elderly, chronic stress, altered circadian rhythms, inflammatory cytokines, and use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. In particular, cortisol and melatonin circadian rhythms are altered, at least in rheumatoid arthritis (RA), and partially involve sex hormone circadian synthesis and levels as well. Abnormal regulation of aromatase activity (i.e., increased activity) by inflammatory cytokine production (i.e., TNF‐alpha, IL‐1, and IL‐6) may partially explain the abnormalities of peripheral estrogen synthesis in RA (i.e., increased availability of 17‐beta estradiol and possible metabolites in synovial fluids) and in systemic lupus erythematosus, as well as the altered serum sex‐hormone levels and ratio (i.e., decreased androgens and DHEAS). In the synovial fluids of RA patients, the increased estrogen concentration is observed in both sexes and is more specifically characterized by the hydroxylated forms, in particular 16alpha‐hydroxyestrone, which is a mitogenic and cell proliferative endogenous hormone. Local effects of sex hormones in autoimmune rheumatic diseases seems to consist mainly in modulation of cell proliferation and cytokine production (i.e., TNF‐alpha, Il‐1, IL‐12). In this respect, it is interesting that male patients with RA seem to profit more from anti‐TNFalpha strategies than do female patients.

Dialogue between the CNS and the immune system in lymphoid organs

Abstract It is well known that the CNS influences the responses of the immune system via humoral substances such as cortisol. Here, Rainer Straub and colleagues discuss aspects of the local interaction between nerves and immune cells in lymphoid organs. They provide evidence for chemically mediated transmission between nerves and immune cells in the spleen which is modified by the microenvironment.

The role of the sympathetic nervous system in intestinal inflammation

The nervous system in the intestine controls motility, secretion, sensory perception, and immune function. Peptidergic neurones with neurotransmitters such as substance P and nerve growth factors have been the main focus of neuroimmunomodulation research in the gut. This review summarises the present knowledge concerning the role of the sympathetic nervous system (SNS) in modulating intestinal inflammation. The role of the SNS for gut inflammation is compared with its role in rheumatoid arthritis which demonstrates notable similarities. Nerve fibres of the SNS not only enter the enteric plexuses but also innervate the mucosa and gut associated lymphoid tissue (GALT). The SNS has pro- and anti-inflammatory functions. Neurotransmitters such as norepinephrine, adenosine, and others can evoke remarkably different opposing effects depending on concentration (presence of sympathetic nerve fibres and extent of neurotransmitter release), receptor affinity at different receptor subtypes, expression of adrenoceptors, availability of cotransmitters, and timing of SNS activity in relation to the inflammatory course. This review attempts to integrate the different perspectives of the pro- and anti-inflammatory effects of the SNS on inflammatory disease of the gut.

Neurotransmitters of the sympathetic nerve terminal are powerful chemoattractants for monocytes.

Macrophages in lymphoid organs are in close contact to nerve terminals of the sympathetic nervous system. Hence, these cells could be targets of neuronal modulation. We studied sympathetic neurotransmitters as chemoattractants enabling the aggregation of macrophages and nerve terminals. Norepinephrine (NE), neuropeptide Y (NPY), isoproterenol (β‐adrenergic), p‐aminoclonidine (α2‐adrenergic), methoxamine (α1‐adrenergic), and adenosine triphosphate (ATP) were used to study human monocyte and macrophage migration in 48‐well Boyden chambers. NE stimulated chemotaxis of monocytes and macrophages at an optimal concentration of 10−10 M (P < 0.025). Isoproterenol, but not p‐aminoclonidine or methoxamine, induced chemotaxis of monocytes (10−10 M, P < 0.05). In these studies, elevation of cAMP is a critical step in NE‐induced chemotaxis of monocytes. NPY (10−11 M, P < 0.05) stimulated monocyte chemotaxis as well. ATP at 10−4 and 10−5 M stimulated undirected cell mobility (P < 0.05). All tested neurotransmitters of the sympathetic nerve terminal were potent chemoattractants. These findings may explain the close association of nerves and macrophages in tissue and lymphoid organs and may thus be of functional relevance in neuroimmunomodulation. J. Leukoc. Biol. 67: 553–558; 2000.

Relevance of Neuropeptide Y for the neuroimmune crosstalk

Both cellular and humoral functions of the immune system are modulated by the sympathetic nervous system (SNS). This interaction is mainly mediated by the release of catecholamines (CA) and their receptor-specific action on immune cells. However, neuropeptide Y (NPY), also present in sympathetic nerve terminals, is released upon SNS-stimulation. NPY modulates potent immunological effects in vitro and in vivo, such as differentiation of T helper cells, monocyte mediator release, NK cell activation, and immune cell redistribution. In addition to this direct action within the neuroimmune crosstalk, NPY is also able to modulate the immunomodulatory effects of other neurotransmitters, thereby acting as a neuroimmune co-transmitter. This review will discuss key findings from recent studies, provide implications for the clinical situation, and integrate the pleiotropic functions of NPY in the context of neuroimmune interactions.