INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
Vol. 27, no. 2,163-167 (2014)
EDITORIAL
CORTICOTROPIN-RELEASING HORMONE, MICROGLIA AND MENTAL DISORDERS S.K. KRITAS 1, A. SAGGINP·G. CERULLP,A. CARAFFA\ P.ANTINOLFI\ A. PANTALONES, M. ROSATI6, M. TEP, A. SPEZIALP, R. SAGGINF and P. CONTI8 Department ofMicrobiology and Infectious Diseases, School of Veterinary Medicine, Aristotle University ofThessaloniki, Macedonia, Greece,' 'Department ofDermatology, University ofRome Tor Vergata, Rome, Italy; 'Nicola S Foundation, Onlus, Arezzo, Italy; 'Orthopedic Division, University ofPerugia, Perugia, Italy; 'Orthopedic Division, University ofChieti-Pescara, Chieti, Italy; "Gynecology Clinic, Pescara Hospital, Pescara, Italy; 'Department ofNeurosciences and Imaging, Faculty ofMedicine and Surgery, G. d'Annunzio University Chieti-Pescara, Chieti, Italy; "Immunology Division, Medical School, University ofChieti-Pescara, Chieti, Italy
J
Received April 28, 2014 - Accepted June 15, 2014 Microglia derive from mononuclear myeloid progenitors and are a major glial complement of the central nervous system. When microglia are activated they secrete inflammatory cytokines and toxic mediators which amplify the inflammatory response. In addition, the microglia inflammatory products are implicated in the neuronal destruction usually observed in various neurodegenerative diseases. Microglia cells express corticotropin releasing hormone (CRH) receptors, and activation of microglia by CRH releases bioactive molecules which have a biological effect in the brain and regulate several neurological diseases. CRH plays a pivotal role in stress responses and is a key mediator of the hypothalamic-pituitary-adrenocortical system. CRH is expressed in human mast cells, leading to autocrine effects and participates in inflammatory response together with neuropeptides, and stimulates mast cells. IL-33-activated mast cells release vascular endothelial growth factor in response to CRH and act synergistically to increase vascular permeability. CRH also up-regulates IL-18 expression by increasing intracellular reactive oxygen in microglia cells. Here we report the relationship between CRH, microglia and mental disorders. Microglia, described and named by Rio Hortega in 1932, are a major glial component of the central nervous system and are immune effector cells that are derived from mononuclear myeloid progenitors distributed ubiquitously in the central nervous system (1). In physiological brain, microglia are in a resting
state, with characteristic small cell bodies and highlyramified cellular processes and they interact with neurons, astrocytes and vascular endothelial cells. When microglia cells are activated by any insult, they undergo morphological changes and become phagocytic cells (2). Activated microglia secrete inflammatory
Key words: microglia. inflammation, brain disorders, immune system, cytokines Mailing address: Spyridon K. Kritas, DVM, PhD, Dip!. ECPHM Associate Professor, Department of Microbiology and Infectious Diseases, School of Veterinary Medicine, Aristotle University ofThessaloniki, 54124 Thessaloniki, Macedonia, Greece Te!.lFax: +30 2310 999940 e-mail:
[email protected]
0394-6320 (2014)
163
Copyright © by BIOLIFE. s.a.s. This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties
DISCLOSURE: ALL AUTHORS REPORT NO CONFLICTS OF INTEREST RELEVANT TO THIS ARTICLE.
164
S.K. KRITAS ET AL.
cytokines and toxic mediators such as nitric oxide, protease and oxygen radicals, which might amplify the inflammatory responses (3), although, the mechanism of activation remain controversial. Induction through MAPK pathways has been studied using a microglia cell line in vitro (4). Microglia are critically involved in various injuries and diseases of the central nervous system (CNS) and release certain cytokines, nitric oxide (NO), brainderived neutrophic factor (BDNF), oligodendrocyte glycoprotein (OMgp), interleukin (lL)-18, tumor necrosis factor-a (TNF-a), IL-l~, IL-6 and IL10, becoming either reparative or harmful for the injured brain (5). The activation of microglia cells and their inflammatory products are implicated in the neuronal destruction commonly observed in various neurodegenerative diseases. Therefore, the production of these inflammatory mediators is a result of the failure of the immune system and is associated with various brain disorders (6). Microglia cells, also express corticotropin releasing hormone (CRH) receptors and activation of microglia cells by CRH release some bioactive molecules, which have biological effects in the brain and play an important role in regulating several neurological diseases (7). It has been previously reported that activated microglial cells express high levels of CRH-Rl (8), which is usually thought to be expressed in neurons. CRH is also released from the hypothalamus, and plays a pivotal role in stress responses as a key mediator of the hypothalamicpituitary-adrenocortical system (9). CRH is a 41-amino-acid neuropeptide, and plays an important role in several mental disorders including stress (10) and chronic fatigue syndrome. CRH has been implicated in the regulation of neuronal cell survival, exerting either neurotoxic or neuroprotective effects. CRH has also the ability to stimulate the secretion of the pituitary adrenocorticotropic hormone (ACTH), which stimulates the synthesis and release ofglucocorticoids
by the adrenal cortex (11). It has been found that it is an important mediator of the hypothalamicpituitary-adrenal (HPA) axis response to stress, and is also expressed by the central nervous system, skin, blood vessels, skeletal muscle. In addition, by acting at specific receptors on multiple populations of immune cells to produce a wide range of effects, CRH is a peptide that regulates behavioral and immunologic challenges (12). The secretion of adrenocorticotropic hormone by CRH, triggers cortisol secretion from the adrenal glands (11). Therefore, it is also implicated in the regulation of neuronal cell survival and has the ability to facilitate the outgrowth of axon in spinal neurons, with therapeutic implications. The biological effects of CRH are mediated via the specific binding to G protein-coupled receptors derived from two diverse genes, CRH-Rl and CRH-R2 (13). CRH-Rl is expressed in human skin, cerebellum, cerebral cortex, and brain stem; while CRHR2 is the predominant receptor expressed in microglia cultures (14). Recently, two new members of the CRH family have been identified, Ucn II and Ucn III (15). Both bind selectively to CRH-R2 with high affinity and have distinct localizations in the brain and periphery (16). CRH-Rl binds to CRH in the brain and has been found in murine microglial cell line (17). CRH-Rl is linked to skin diseases where it regulates coetaneous immune cells, and the endocrine system and has also been found in the synovium of rheumatoid arthritis (RA) patients and resting immune normal cells from thymus and spleen (18). In recent years several reports have shown that activated mouse microglia induced by endotoxin or hypoxia, express high levels of CRH-Rl (19), which therefore, is typically expressed in neurons. CRH is an active molecule in the regulation of a number of neural activities under both physiological and pathological conditions. In addition, activation of microglia cells (accompanied by an increase in
Table I. Involvement ofmicroglia in inflammation.
Mononuclear myeloid progenitors7microglia immune effector cells7activation7phagocitic cells7production7inflammatory cytokines (IL-l, TNF, IL-6, IL-18); nitric oxide; protease; oxygen radicals7 Inflammation
lot. J. ImmuoopatboL PbarmacoL
the brain CRH and its receptors) might contribute to the pathogenesis of neurodegenerative disorders and precedes or is concomitant with glia cell degeneration in neurological disorders such as Autism Spectrum Disorders (ASD), Alzheimer, Parkinson, stroke, brain traum, multiple sclerosis and AIDS (20) We previously reported that stress molecules include CRH and NT, secreted in response to the metabolic burden. These molecules may act through mast cells, especially because they are expressed in human mast cells leading to autocrine effects. (21). Many triggers participate in inflammation together with neuropeptides secreted locally that stimulate mast cells. Mast cells can also be activated by various immune triggers such as chymase and tryptase, stem cell factor (SCF) and TNF, TLR ligands, immunoglobulin light chain, and IL-33 which induces mast cell production of IL-13 and promotes their survival (22). We previously showed that IL-33 augments human mast cell release of
165
vascular endothelial growth factor (VEGF) in response to CRH, and NT act synergistically to increase vascular permeability (22). Neuropeptides can also activate mast cells in a receptor-independent manner by activating G proteins directly (23). IL18 is a pleiotropic immunostimulatory cytokine, expressed by a variety of cell types and tissues including microglia and astocytes and brain diseases (24). IL-18 is involved in the inflammatory and neurodegenerative processes in the brain and is regulated partially by CRH. In fact, CRH upregulates IL-18 expression by increasing the intracellular reactive oxygen intermediates levels in microglial cells (25). We have also previously shown that mast cell-derived vasoactive, pro-inflammatory and neurosensitizing molecules could act on keratinocytes, endothelial cells or nerve endings to liberate additional molecules and lead to chronic inflammation and neuropathic hypersensitivity
Table II. Involvement ofCRH in the pathophysiological mechanism ofinflammation. CRH~CRHR~Mast
cell
actvation~TNF,
IL-6,
IL-8
and
IL-33
release~PMNs
recruitment-s Inflammation
Table III. Biological effects ofCRH.
-Microglia activation through some bioactive molecole -Regulates several neurological diseases -Plays pivotal role in stress -Mediates several mental disorders -It is involved in chronic fatigue syndrome -Exerts neurotoxic or neuroprotective effects -Stimulates the secrition ofA CTH -Has the ability to facilitate the outgrowth ofaxon -It is involved in skin diseases -Regulates coetaneuos immune cells and endocrine system -It is involved in rheumatoid arthritis -Regulates a number ofneural activities -Contributes to the pathogenesis ofAlzheimer, Parkinson, stroke, Multiple Sclerosis, and AIDS -Partially regulates IL-8 -Increases intracellular reactive oxigen -It is involved in behavioral and immunological challenges
166
S.K. KRITAS ET AL.
(26). Therefore, CRH has been involved in several inflammatory skin conditions, including atopic dermatitis (AD) and psoriasis, which are exacerbated by stress (27). Neuronal stimulation, such as that occurring during stress, leads to secretion ofmany neuropeptides that can activate mast cells. Neuropeptides such as substance P (SP), NGF, neurotensin (NT), pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), can activate mast cells and can lead to mast cell-dependent granulocyte infiltration directly through the synthesis ofTNF-a, IL-8 or IL-33 (28). Mast cell activation by neuropeptides acts through specific receptors, such as receptors for NT or tachykinin NK] receptors (29). It has been reported that acute stress can activate dura mast cells and increase vascular permeability through activation of NK 1 receptors, without stimulation (30). The relationship between CRH and mast cells in physiological and pathological tissue and how CRH is regulated is unclear. However, CRH RI and CRH R2 agonists and antagonists in inflammatory, coetaneous and neurodegenerative diseases, may have a potential therapeutic impact.
6. 7.
8.
9.
10.
II.
REFERENCES 12. I.
2. 3.
4.
5.
Horiuchi M, Wakayama K, Itoh A, Kawai K, Pleasure D, Ozato K, Itoh T. Interferon regulatory factor 8/ interferon consensus sequence binding protein is a critical transcription factor for the physiological phenotype of microglia. 1 Neuroinflammation 2012; 9:227. Vilhardt F. Microglia: phagocyte and glia cell. Int 1 Biochem Cell Bioi 2005; 37( I): 17-21. Zhu W, Zheng H, Shao X, Wang W, Yao Q, Li Z. Excitotoxicity of TNF alpha derived from KA activated microglia on hippocampal neurons in vitro and in vivo. 1 Neurochem 2010; 114(2):386-96. Potucek YD, Crain 1M, Watters 11. Purinergic receptors modulate MAP kinases and transcription factors that control microglial inflammatory gene expression. Neurochem Int 2006; 49(2):204-14. Du F, Yin L, Shi M, Cheng H, Xu X, Liu Z, Zhang G, Wu Z, Feng G, Zhao G. Involvement of microglial cells in infrasonic noise-induced stress via upregula-
13.
14.
15.
16. 17.
ted expression of corticotrophin releasing hormone type I receptor. Neuroscience 2010; 167(3):909-19. Welling LC, Figueiredo EG. World Neurosurgery 20 I0; 74(4-5):388-89. Stevens SL, Shaw TE, Dykhuizen E, Lessov NS, Hill 1K, Wurst W, Stenzel-Poore MP. Reduced cerebral injury in CRH-RI deficient mice after focal ischemia: a potential link to microglia and atrocytes that express CRH-RI. 1 Cereb Blood Flow Metab 2003; 23(1O):1l51-59. Wang W, 1i P, Dow KE. Corticotropin-releasing hormone induces proliferation and TNF-alpha release in cultured rat microglia via MAP kinase signalling pathways. 1 Neurochem 2003; 84(1):189-95. Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol 2005; 67:259-84. Theoharides TC, Asadi S, Patel AB. Focal brain inflammation and autism. 1 Neuroinflammation 20 I; 10:46. Meaney M1, Diorio 1, Francis D, Widdowson 1, LaPlante P, Caldji C, Sharma S, Seckl 1R, Plotsky PM. Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev Neurosci 1996; 18(1-2):49-72. Forsythe P. The nervous system as a critical regulator of immune responses underlying allergy. CUffPharm Des 2012; 18(16):2290-304. Kasckow 1, Mulchahey 11, Aguilera G, et al. Corticotropin-releasing hormone (CRH) expression and protein kinase A mediated CRH receptor signalling in an immortalized hypothalamic cell line. 1 Neuroendocrinol2003; 15(5):521-9. Slominski A, Zbytek B, Zmijewski M, Slominski RM, Kauser S, Wortsman 1, Tobin D1. Corticotropin releasing hormone and the skin. Front Biosci 2006; II :2230-48. Zoumakis E, Kalantaridou SN, Makrigiannakis A. CRH-like peptides in human reproduction. CUffMed Chern 2009; 16(32):4230-5. Venihaki M, Majzoub 1. Lessons from CRH knockout mice. Neuropeptides 2002; 36(2-3):96-102. Vila G, Papazoglou M, Stalla 1, Theodoropoulou M, Stalla GK, Holsboer F, Paez-Pereda M. Sonic hedgehog regulates CRH signal transduction in the
Int. J. ImmunopatboL PbarmacoL
adult pituitary. FASEB J 2005;19(2):281-3. 18. McEvoy AN, Bresnihan B, FitzGerald 0, Murphy EP. Corticotropin-releasing hormone signaling in synovial tissue from patients with early inflammatory arthritis is mediated by the type 1 alpha corticotropinreleasing hormone receptor. Arthritis Rheum 2001; 44(8):1761-7. 19. Popa-Wagner A, Badan I, Vinti1escu R, Walker L, Kessler C. Premature cellular proliferation following cortical infarct in aged rats. Rom J Morpho1 Embryo1 2006; 47(3):215-28. 20. Kern JK, Geier DA, Audhya T, King PG, Sykes LK, Geier MR. Evidence of parallels between mercury intoxication and the brain pathology in autism. Acta Neurobio1 Exp (Wars) 2012; 72(2):113-53. 21. Sismanopou1os N, De1ivanis DA, Mavrommati D, Hatziage1aki E, Conti P, Theoharides TC. Do mast cells link obesity and asthma? Allergy 2013; 68(1):815. 22. Theoharides TC, Zhang B, Kempuraj D, et al. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Nat! Acad Sci USA 2010; 107(9):4448-53. 23. Mous1i M, Bueb JL, Bronner C, Rouot B, Landry Y. G protein activation: a receptor-independent mode of action for cationic amphiphi1ic neuropeptides and venom peptides. Trends Pharmaco1 Sci 1990; 11(9):358-62.
167
24. Aarli JA. Role of cytokines in neurological disorders. CurrMedChem2003; 10(19):1931-7. 25. Yang Y, Hahm E, Kim Y, et al. Regu1ationof IL18 expression by CRH in mouse microglial cells. Immuno1 Lett 2005; 98(2):291-96. 26. Theoharides TC, Donelan JM, Papadopou1ou N, Cao J, Kempuraj D, Conti P. Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmaco1 Sci 2004; 25(11):563-8 27. Vasiadi M, Therianou A, Sideri K, et al. Increased serum CRH levels with decreased skin CRHR-1 gene expression in psoriasis and atopic dermatitis. J Allergy Clin Immuno12012; 129(5):1410-13. 28. Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 2008; 123(3):398-410. 29. Rijnierse A, van Zijl KM, Koster AS, Nijkamp FP, Kraneveld AD. Beneficial effect of tachykinin NK1 receptor antagonism in the development of hapteninduced colitis in mice. Eur J Pharmacol 2006; 548(1-3): 150-57. 30. Kandere-Grzybowska K, Gheorghe D, Priller J, Esposito P, Huang M, Gerard N, Theoharides TC. Stress-induced dura vascular permeability does not develop in mast cell-deficient and neurokinin-I receptor knockout mice. Brain Res 2003; 980(2):21320.
