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Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis

Abstract

Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.

Introduction

Converging sources of evidence point to a role for inflammation in the development of depression, fatigue, and cognitive dysfunction.1, 2, 3, 4, 5, 6 The major role of proinflammatory cytokines has been well characterized, allowing to demonstrate that they interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity and neurocircuits relevant to mood regulation. Studying patients treated with interferon alpha has been very fruitful in this regard.7 Besides, cell-mediated immune activation has been highlighted in depression, with an emphasis on activated T lymphocytes, peripheral macrophages, microglial, astroglial cells and their interactions with glial cells.8, 9, 10 The roles of other immune cells are underexplored. We focus here on mast cells, whose residence in perivascular locations on the brain side of the blood–brain barrier indicates that they are strategically situated to initiate microglial, neural and vascular responses.11, 12, 13 Mast cells are innate immune cells involved in homeostasis maintenance and immune response regulation.14 Mast cell activation induces the release of various molecules contained in their cytoplasmic granulations, such as histamine, serotonine (5-HT), tryptase, prostaglandin, cytokines and chemokines.14 They are able to secrete proinflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6 and IL-18. Indeed they sit at major crossroads for both innate and adaptative immune responses.14 So far few articles have studied mast cells' involvement in anxiety and other psychiatric conditions.12, 15, 16

We studied here patients with mastocytosis, a rare condition characterized by an accumulation and activation of mast cells in various tissues.17 It is usually indolent but in some cases exhibits aggressive features and is associated to other clonal hematological malignancies.17, 18 We and others have shown that 4−60% of mastocytosis patients present with neuropsychiatric manifestations including depression, and attention as well as memory impairments.19, 20, 21, 22, 23

In inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) activation induces tryptophan (TRP) catabolism, resulting in a decrease of 5-HT synthesis and an increase of kynurenine (KYN) formation, which in turn is metabolized in kynurenic acid (KA) and quinolinic acid (QA), as well as other metabolites such as hydroxykynurenine, anthralinic acid and eventually picolinic acid. This subversion of TRP metabolism correlates with depression in interferon alpha-treated patients.24, 25 As mastocytosis represents a paradigm of mast cell activation, we decided to study a cohort of 54 patients with proven mastocytosis (N=54) and compared patients’ levels of TRP, 5-HT, KYN, IDO1 activity, KA and QA with the same metabolites and enzyme levels in healthy control subjects (N=54). Our study would pinpoint mast cells' involvement in inflammation pathways linked to depression.26

Materials and Methods

Patients

Adults with a diagnosis of mastocytosis (N=54) and a mean age of 50.1 years were enrolled in a prospective multicentric French study between 2007 and 2011 (Table 1). They consisted of 66.7% women. All patients provided their informed consent. The study was approved by the ethical committee at Necker hospital, and was carried out in compliance with the precepts of the Helsinki protocol. To establish the diagnosis of mastocytosis, following international WHO criteria, we provided measurements of tryptase serum level as previously described, as well as those obtained during a search for KIT gene mutations in the skin and/or bone marrow.27 Indolent forms of mastocytosis were present in 88.9% of patients (46 ISM, 2 CM) and aggressive forms in 11.1% (4 agressive systemic mastocytosis, 2 systemic mastocytosis with associated hematological non mast cell disease). The median tryptase level in patients was 31.9 ng l−1 (mean 101.3 ng l−1), significantly higher than controls (P<0.0001). The D816V genotype was present in 75.9% of patients (n=41).

Table 1 Main features of the study population (N=54)

Psychological analysis

Depression and stress

Participants completed the French version of Beck Depression Inventory (BDI-II), a 21-item self-report questionnaire designed to measure the severity of depression symptoms.28 Total score indicates the severity of participant's depression symptoms: doubtful−minimal (0–9), mild (10–18), moderate (19–29) or severe (30–63). To consider patients as depressed a score of 10 was adopted as the cutoff point; to discriminate patients with mild and moderate−severe depression, the cutoff score of 19 was adopted.29 Stress was assessed by the Perceived Stress Scale, which measures the degree to which life events are appraised as stressful by individuals.30

TRP, 5-HT, KYN, KA and QA measurements

Blood samples were collected in 7- ml Vacutainer (Becton-Dickinson, Le Pont de Claix, Isère, France) collection tubes containing heparin or EDTA. Except for 5-HT measurement, the tubes were centrifuged at 2500 g and 4 °C for 15 min, and the separated plasma was aliquoted in 0.5-ml fractions into 1.5-ml polypropylene vials (Corning, NY, USA), and then frozen at −80 °C until analysis.

Plasma TRP and whole-blood 5-HT rates were determined by high-performance liquid chromatography using the method of Kema et al.31 KYN and KA were measured using high-performance liquid chromatography as described by Fujigaki et al.32 and Swartz et al.,33 respectively, whereas QA was measured using mass fragmentography.34 The KYN/TRP ratio was calculated from absolute concentrations of KYN and TRP and was used as an index of IDO1 activity. We compared levels of 5-HT, TRP, IDO1, KYN, KA and QA between the 54 patients and 54 age-matched healthy controls (with neither psychological affection nor mastocytosis) (Table 1). Taking as thresholds the 90th percentiles of a large (n=416) control cohort,35 TRP was considered low when its rate was <45 μm; IDO1 activity was considered high if >7.5% and 5-HT levels were considered low if under 150 nm.

Plasma interferon gamma (IFN-γ) was measured using an electrochemiluminescent immunoassay (MSD, Rockville, MD, USA).36

The detection limits, and intra- and inter-assay variabilities can be found in Supplementary Table S1.

Statistical analysis

Two-tailed Wilcoxon matched paired tests and correlations by the linear regression method were performed using GraphPad Prism software version 5.01 (GraphPad Software, San Diego, CA, USA) and ‘R’ statistical software (www.r-project.org). Considering the preferential involvement of QA in depression pathophysiology in comparison with KA,37, 38, 39, 40 one-tailed Wilcoxon test was performed to compare QA and KA patient/control ratios.

Results

Main neuropsychological features

Among the 54 patients with mastocytosis, mean depression score was 16.5 (range=0–45) and 66.7% of patients displayed a depression score 10, including 20 mild-depression patients and 16 moderate-to-severe-depression patients (Table 1). Perceived stress in our sample was high (mean=38.3; range=37–63), with 46.3% of patients displaying a score 40.

Higher IDO1 activity and lower levels of TRP and 5-HT in mastocytosis

In our study cohort, 59.3% (n=32) of patients presented abnormally low levels of TRP, 48.1% (n=26) high IDO1 activity and 33.3% (n=18) low 5-HT levels. None of our patients displayed malabsorption, especially neither severe digestive mastocytosis, which could explain low TRP absorption, nor hypoalbuminemia. Patients displayed lower levels of TRP and 5-HT than controls (respectively, P<0.0001 and P<0.001) and higher IDO1 activity (P<0.01) and higher levels of KA and QA (respectively, P<0.01 and P<0.0001) (Figure 1). KYN was significantly lower among patients (P<0.05). In order to compare KA and QA pathways, we computed the difference (ratio) between patients and controls in the KA/KYN ratio and compared it with the difference between patients and controls in the QA/KYN ratio. KYN metabolism was preferentially oriented towards QA, with an increase in the QA/KYN ratio in patients that was significantly larger than the increase in the KA/KYN (P<0.05).

Figure 1
figure1

Comparison of tryptophan, serotonin, kynurenin, indoleamine 2,3-dioxygenase 1 (IDO1) activity, kynurenic acid and quinolinic acid between patients and controls. We compared patients and controls using the Wilcoxon test; all differences were significant.

PowerPoint slide

Patients with high perceived stress and high depression scores present high IDO1 activity and low TRP

Whole-blood 5-HT levels did not correlate with depression score (P>0.8). Instead, depression score negatively correlated with plasma levels of TRP (P0.0001) and positively correlated with plasma IDO1 activity (P0.0001) (Figure 2). Neither correlation was found with plasma KA or QA levels.

Figure 2
figure2

Correlations between depression scores and tryptophan and indoleamine 2,3-dioxygenase 1 (IDO1) activity levels. Pearson correlations were confirmed with linear regression. Higher depression score correlated with both lower levels of plasma tryptophan (in μmol l−1) (r2=0.42; P<0.0001) and higher plasma IDO1 activity (in %) (r2=0.32; P<0.0001).

PowerPoint slide

Neither age nor BMI correlated significantly with IDO1, TRP or BDI (all P>0.4). Adding age and BMI as independent variables in these correlations indicated that keeping age and BMI constant, depression (BDI scores) still correlated negatively with TRP (P<0.0001) and positively with IDO1 (P<0.0001). An interaction analysis using BMI category (according to BMI median split) showed no interaction between BMI category and these correlations (P>0.25). A similar interaction analysis using age category (according to age median split) showed that the slopes of the correlation lines with depression for the group of older patients was significantly smaller that that for the younger patients for TRP (P<0.05) and marginally so for IDO1 (P=0.083). Crucially, negative correlation between depression and TRP and positive correlation between depression and IDO1 remained significant in each age group (P<0.0001 and P<0.0001 in older patients, and P<0.01 and P<0.05 in younger patients).

IFN-γ is considered to be the most potent inducer of IDO1,41 and was found to be higher in patients than in controls in our study (P<0.0001). We therefore evaluated the effect of IFN-γ on the above results. IFN-γ did not correlate with depression and IDO1 (P>0.5). Moreover, introducing IFN-γ as a cofactor in the correlation analyses did not alter the correlations between depression and TRP or IDO1, which remained significant (both P<0.0001). Therefore, the correlations found between BDI and TRP and IDO1 do not appear to be mediated by IFN-γ.

We compared depressed patients (score 10, n=36) with non-depressed patients (n=18), and patients with high perceived stress (scores 40, n=25) with patients with low perceived stress in regard to 5-HT, TRP, KA and QA. We first noted that there was some correlation between high depression scores and high stress scores, with depressed patients presenting significantly higher levels of perceived stress (mean=43.0 versus 29.1; P<0.01) and high-stress patients presenting higher levels of depression (mean=23.5 versus 10.5; P<0.01).

With regard to biological measures, depressed patients presented significantly lower plasma TRP levels than controls (mean=39.7 versus 45.6; P<0.05). Patients with high perceived stress displayed significantly higher levels of plasma IDO1 activity (mean=9.5 versus 6.9; P<0.01) and lower plasma TRP levels (mean=37.2 versus 45.6; P<0.01). No significant difference was found for plasma KYN or KA or QA levels (all P>0.2).

Discussion

In this study we aimed to demonstrate mast cells' potential involvement in inflammation pathways linked to depression pathophysiology. Mastocytosis, a rare disease with mast cell accumulation and activation, provided us a unique condition to reach this goal. Depression and cognitive impairment are frequent and associated with disability in patients with mastocytosis.19, 20, 21 In a large cohort of patients with mastocytosis, we focused on a physiological pathway: TRP metabolism. We demonstrated that patients displayed significantly higher plasma IDO1 activity, higher levels of plasma KA and QA, and lower levels of plasma TRP and whole-blood 5-HT as compared with healthy individuals. Moreover, IDO1 activity and TRP levels correlated with perceived stress and depression scores.

These results are reminiscent of previous studies performed in patients with inflammation-induced depression. The role of proinflammatory cytokines such as interferon alpha, TNF or IL-6 has been repeatedly demonstrated among interferon-alpha-treated patients, in depression with elevated C-reactive protein level, and in experimental proinflammatory challenges such as endotoxin injection or vaccine.42, 43, 44, 45, 46, 47, 48, 49, 50, 51 Inflammation pathways include TRP metabolism through IDO1 activation, leading to abnormal accumulation of KYN catabolites linked to depressive symptoms.1, 8

Few articles have focused on cells involved in these cascades. Besides activated T lymphocytes or peripheral macrophages and microglial changes, few data are available regarding the role of mast cells.1, 9, 10, 52 Here, our results on the study of TRP metabolism in a rare condition, mastocytosis characterized by mast cell accumulation and activation, and a high prevalence of depression and cognitive impairment, suggest that directly or indirectly mast cells may be involved in psychiatric manifestations of inflammation.17, 19

The brain contains numerous mast cells, which are located along vessels, preferentially near the blood−brain barrier on the side of the brain.12 Mast cells are also located in high density in the hypothalamus, which is involved in systems of stress response, emotion and cognition, as well as in amygdales and in the thalamus, lesions or stimulation of which have been associated with changes in emotional reactivity and pain.53, 54, 55, 56 Because of their specific distribution and density in the brain, mast cells' over-activity may interfere with brain function and adversely affect stress response, cognition and emotionality.16, 57, 58, 59, 60 Mast cells can secrete proinflammatory cytokines such as TNFα, IL-1 and IL-6, and are able to express IDO1.14 Moreover, it has recently been shown that KYN catabolites are able to activate mast cells.61, 62, 63 This phenomenon could induce a vicious circle by activating more mast cells, which in turn will secrete proinflammatory cytokines leading to IDO1 activation. Considering their location in the brain and their relation with proinflammatory cytokines both as provider and as target, mast cells could trigger inflammation-induced depression. Moreover, in a cross-diagnostic fashion, mastocytosis could be considered a model disease to study inflammation-induced depression; studying patients treated with interferon alpha has also been very fruitful in this regard.12

As far as treatment is concerned, targeting cytokines such as TNFα, IL-1 or IL-6 might reduce mood and cognitive impairment in systemic inflammation.47, 64, 65, 66, 67, 68 As shown in a previous study in mastocytosis,69 we found low 5-HT levels in patients, a result that can be here explained by TRP metabolism deviation towards the KYN pathway. Low 5-HT levels might actually contribute to the burden of depression and cognitive impairment. Musselman et al.42 demonstrated that treatments targeting 5-HT transmission, such as paroxetine, a selective serotonin reuptake inhibitor, can reduce depression incidence among interferon alpha-treated patients. Similarly, citalopram, another selective serotonin reuptake inhibitor, can prevent endotoxin-induced fatigue.70 However, correcting low serotoninemia may not be sufficient to improve all symptoms as it does not target KYN metabolism. Reducing IDO1 activity could avoid deviating TRP metabolism towards the KYN pathway. In preclinical data, the IDO1 antagonist, 1-methyl TRP, has been shown to abrogate the impact of lipopolysaccharides as well as infection with bacille Calmette–Guerin on depressive-like behavior.71 Considering the detrimental effect of IDO1-mediated TRP depletion on T-cell function, 1-methyl TRP is currently being tested in patients with advanced-stage cancers (eight ongoing trials according to ClinicalTrials.gov) to restore immune functions against cancer cells.72

Cholinergic blockade by KA, a KYN catabolite, could also be solved by alpha7 nicotinic acetylcholine receptor agonists.73 This strategy is also in line with the currently approved vagus nerve stimulators in depression.74 We observed a significant imbalance towards QA in comparison with KA. This last result is in line with the NMDA receptor agonist effect of QA leading to neurotoxic effects via lipid peroxidation, and disruption of the blood–brain barrier, while KA might have neuroprotective effects.37, 38, 75 As stressed on by Capuron and Miller,3 ketamine, an NMDA antagonist, allows a rapid and dramatic improvements in mood in patients with treatment-resistant depression and could target inflammation-induced depression.76, 77, 78 Given the preferential increase of QA levels in comparison with KA levels in mastocytosis patients, this therapeutic strategy might be efficient in mastocytosis patients displaying stress and depression.

Finally, as we demonstrated here mast cells' potential involvement in inflammation-induced depression, clinical trials could be performed in the near future in order to test the efficacy of molecules that target mast cells, such as tyrosine kinase inhibitors (Figure 3).20, 79

Figure 3
figure3

Hypothetical tryptophan (TRP) metabolism in mastocytosis. Cytokines (interleukins 1 and 6, tumor necrosis factor α) synthetized by activated mast cells in mastocytosis are able to induce the enzyme indoleamine-2,3-dioxygenase (IDO1) that catabolizes TRP into kynurenine (KYN) and then quinolinic acid, thereby reducing the availability of TRP for 5-HT synthesis via the enzyme TRP hydroxylase. The activation of the KYN pathway may also be due to the induction of the liver enzyme TRP dioxygenase by increased cortisol secretion in case of stress.

PowerPoint slide

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Acknowledgements

Sophie Georgin-Lavialle is a recipient of a grant from SNFMI-Genzyme-maladies rares and Centre National de la Recherche Scientifique (CNRS) and Assistance Publique Hôpitaux de Paris (AP-HP). Daniela S Moura is a recipient of a grant from the Cancéropôle Ile-de-France (Appel d’Offre SHS 2009). Jean-Christophe Chauvet-Gélinier is supported by a Program Hospitalier de Recherche Clinique Interrégional grant (PHRC-IR 2009), GIRCI Est, France.

Author contributions

DSM, RG, J-ML, OH, SG-L, AS: study concept and design. SG-L, DSM, J-ML, J-CC-G, OH, AS: acquisition of data, analysis and interpretation of data. SG-L, RG and AS: drafting of the manuscript. DSM, J-ML, J-CC-G, FC, GD, ES, RG, SB, CG-G, CB, M-AA, AA, OL, BT, EH, PV, J-RT, PD, BB, OH and SG-L: acquisition of data and edition of the manuscript.

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Correspondence to O Hermine or R Gaillard.

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Competing interests

RG has received compensation as a member of the scientific advisory board of Janssen, Lundbeck, Roche, Takeda. He has served as consultant and/or speaker for Astra Zeneca, Pierre Fabre, Lilly, Otsuka, SANOFI, Servier and received compensation, and he has received research support from Servier. AS has consulted for Servier and received compensation. SGL has served as consultant and/or speaker for SOBI and Novartis and received financial help from SOBI and Bayer for travelling to congress. OH received research funding and honorarium from AB Science. The remaining authors declare no conflict of interest.

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French Mast Cell Study Group Odile Beyne-Rauzy, Christian de Gennes, Isabelle Durieu, Olivier Fain, Bernard Grosbois, Isabelle Guichard, Mohamed Hamidou, David Launay, Christian Lavigne, Christina Livideanu, Franck Nicolini, Frederique Retornaz, Michel Arock and Jean-Benoit Arlet.

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Georgin-Lavialle, S., Moura, D., Salvador, A. et al. Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis. Mol Psychiatry 21, 1511–1516 (2016). https://doi.org/10.1038/mp.2015.216

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