A novel aspect for depression and cytokine hypothesis: ‘NLRP3 inflammasome’

Yıl 2013, Cilt: 3 Sayı: 2, 65 - 68, 30.01.2014

Ceren Şahin Feyza Arıcıoğlu

Öz

At present, 1/3 of patients diagnosed with major depression do not respond to the current pharmacological treatments acting on monoaminergic neurotransmission has shown that the monoaminergic hypothesis alone, remains inconclusive for highlighting the pathogenesis of depression. It has been shown by several clinical and experimental studies that high serum plasma levels of proinflammatory cytokines such as IL-1ß, IL-6, TNF-? are related with depressive status. Besides, with the antidepressant treatment acting on serotonergic system, there is a decrease in cytokine levels of depressive patients and antidepressant-like effects are observed with the use of immune suppressant drugs acting on cytokines mediated mechanisms. On the other hand, inflammatory cytokines have been proposed to contribute the increase in activation of hypothalamus-pituitary-adrenal (HPA) axis, in parallel with elevated plasma cortisol levels in depressed patients. With the establishment of cytokine hypothesis in depression, the initiating mechanisms of inflammatory processes have become important issues. NLRP3 inflammasome is a multiprotein complex, known to be responsible for initiating the inflammatory mechanisms mediated with IL-1ß, one of the major proinflammatory cytokine investigated in depression, and also IL-18. It results from the activation of Nod like receptor protein 3 (NLRP3) which is a cytosolic receptor protein especially located in macrophage and microglia. Investigating NLRP3 inflammasome and related pathways in depression could be accepted as an intriguing subject for possibly bringing a new aspect to cytokine hypothesis and further approach for antidepressant therapies.

Key words: Depression, cytokine, proinflammatory, IL-1ß, NLRP3, inflammasome

Anahtar Kelimeler

Depression, cytokine, proinflammatory, IL-1β, NLRP3, inflammasome

Depresyon ve sitokin hipotezinde yeni bir boyut: ‘NLRP3 inflamazomu’

Öz

Günümüzde majör depresyon hastalarının yaklaşık 1/3’ünün monoaminerjik aşırımı kuvvetlendirerek etkilerini gösteren mevcut farmakolojik tedavilere yanıt vermemesi depresyon patogenezinin aydınlatılmasında tek başına monoamin hipotezinin yeterli olmadığını göstermektedir. Klinik ve deneysel çok sayıda çalışma ile depresyon tablosuna artmış serum IL-1ß, IL-6, TNF-? gibi proinflamatuvar sitokin seviyelerinin eşlik ettiği, serotonerjik sistem üzerinden etkisini gösteren antidepresan ilaçlar ile depresyon hastalarında söz konusu sitokin seviyelerinin azaldığı ve sitokin aracılı immün yanıtları baskılayan ajanlarla antidepresan benzeri etkiler elde edildiği gösterilmiştir. Diğer taraftan depresyon hastalarında arttığı gösterilen Hipotalamus-hipofiz-adrenal (HPA) eksenin aktivasyonuna paralel olarak plazma kortizol düzeyleri yükseliklerine inflamatuvar sitokinlerin aracılık ettiği düşünülmektedir. Depresyonda sitokin hipotezinin ortaya konulması ile son yıllarda sitokinler aracılı inflamatuvar süreçleri başlatan mekanizmaların önemi gündeme gelmiştir. NLRP3 inflamazomu; depresyon ile ilişkisi araştırılan proinflamatuvar sitokinlerin başında gelen IL-1ß ve beraberinde IL-18 aracılı inflamatuvar yanıtların başlamasından sorumlu olduğu keşfedilen multiprotein yapıda bir kompleks olup; makrofaj, mikroglia gibi immün sistem hücrelerinin sitozolünde yerleşim gösteren Nod benzeri reseptör proteini 3’ün (NLRP3) aktivasyonu ile meydana gelmektedir. NLRP3 inflamazomu ile ilişkili yolakların aydınlatılması; depresyonda sitokin hipotezine ve antidepresan tedavi yaklaşımlarına yeni bir boyut kazandırabilmesi bakımından ilgi çekici bir konu niteliğini taşımaktadır.

Anahtar Kelimeler : Depresyon, sitokin, proinflamatuvar, IL-1ß, NLRP3, inflamazom

Anahtar Kelimeler

Depresyon, sitokin, proinflamatuvar, IL-1β, NLRP3, inflamazom

Kaynakça

• Iwata M, Ota KT, Duman RS. The inflammasome: Pathways linking psychological stress, depression and systemic illnesses. Brain Behaviour and Immunity. 2013;(in press).
• Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression An emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62: 63-77.
• Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: Rationale and Progress to Date. Drugs. 2012; 9;72(10): 131-1333.
• Simona NM, McNamara K, Chowa CW, Maser RS, Papakostas GI, Pollack MH, Nierenberg AA, Fava M, Wong KK. A detailed examination of cytokine abnormalities in Major Depressive Disorder European Neuropsychopharmacology 2008;18: 230-233.
• Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL. A meta-analysis of cytokines in major depression. Biol. Psychiatry 2010;67: 446-457.
• Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis Neuropsychopharmacology: Official publication of the American College of Neuropsychopharmacology 2011;36: 245224
• Kenis G, Maes M. Effects of antidepressants on the production of cytokines. Int. J. Neuropsychopharmacol. 2002;5: 401-412.
• Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, Zitnik R, Cella D, Krishnan R, Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367: 29Stetler C, Miller GE. Depression and hypothalamic–pituitary–adrenal activation: a quantitative summary of four decades of research. Psychosom. Med. 2011;73: 114-126.
• Berkenbosch F, Van Oers J, del Rey A, Tilders F, Besedovsky H. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science. 1987;238: 524-526.
• Pace TW, Miller AH. Cytokines and glucocorticoid receptor signaling. Relevance to major depression. Ann. N. Y. Acad. Sci. 2009;1179: 86Maes M, Bosmans E, Meltzer HY, Scharpe S, Suy E. Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? Am. J. Psychiatry. 1993;150: 1189-1193.
• Vladimer GI, Marty-Roix R, Ghosh S, Weng D, Lien E. Inflammasome and host defenses against bacterial infections. Current Opinion in Microbiology. 2013;16: 23-31.
• Haneklaus M, O’Neill L AJ, Coll RC. Modulatory mechanisms controlling the NLRP3 inflmmasome in inflammation: recent developments. Current Opinion in Immunology. 2013;25: 40-45.
• Harris J. Autophagy and cytokines. Cytokine. 2011;56: 140-144.
• Harris J. Autophagy and IL-1 family cytokines. Frontiers in Immunology. 2013;4(83): 1-6.
• Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature. 2008;456: 264-268.
• Harris J, Hartman M, Roche C, Zeng SG, O’Shea A, Sharp FA, et al. Autophagy controls IL-1β secretion by targeting pro-IL-1β for degradation. J. Biol. Chem. 2011;286: 9587-9597.
• Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA,Rabinovitch M, Cernadas M, Kim HP, et al. Autophagy proteins regulate innate immune response by inhibiting by the NALP3 inflammasome-mediated mitochondrial DNA release. Nat Immunol. 2011;12: 222-230.
• Sorbara MT, Girardin SE. Mitochondrial ROS fuel the inflammasome. Nature. 2011;21: 558-560.
• Zou R, Yazdi AS, Menu P, Tschopp J. A rol for mitochondria in NLRP3 inflammasome activation. Nature. 2010;469: 221-225.
• Bauernfeind F, Rieger A, Schildberg FA, Knolle PA, Schmid-Burgk JL, Hornung V. NLRP3 inflammasome activity is negatively controlled by miR-2 J Immunol. 2012;189: 4175-4181.
• Arulkumaran N, Unwin RJ, Tam FW: A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin Investig Drugs. 2011;20: 897-915.