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. 2026 Jun 20;16:439. doi: 10.1038/s41398-026-04211-2

Blood IL-6 is a critical trigger of depressive symptoms in a mouse model for human atopic dermatitis

Kenshiro Matsuda 1,11, Ryo Muko 1, Changjong Moon 2, Taekyun Shin 3, Peter D Arkwright 4, Joanne L Pennock 4, Shogo Endo 5, Shuichi Yanai 6, Erika Jensen-Jarolim 7, Akira Shibuya 8, Mitsutoshi Tominaga 9, Kenji Takamori 9, Masa-aki Oikawa 10, Akane Tanaka 1,✉, Hiroshi Matsuda 1,✉
PMCID: PMC13530222  PMID: 42321187

Abstract

Patients with atopic dermatitis (AD) often suffer from mental health issues such as depression. Crosstalk between proinflammatory cytokines and hippocampal circuits may be a potent risk factor for behavioral abnormalities in depression, including anxiety, and mood disorders, which negatively controlled hippocampal neurogenesis via the upregulation of several proinflammatory cytokines. However, the mechanisms by which AD notably contribute to the development of depression are poorly understood. We found that increased IL-6 and soluble IL-6Rα (sIL-6Rα) in the peripheral blood specifically disrupted the blood-brain barrier and triggered depressive symptoms in NC/Tnd mice with spontaneous AD. The skin severity and depressive behavior correlated with markedly reduced numbers of doublecortin (DCX)-positive immature neurons in the hippocampus. Parabiotic pairs of mice with AD and unaffected mice showed disruption of hippocampal neurogenesis in the unaffected mice. Injection of neutralizing mAb against IL-6 significantly improved depressive behavioral signs and hippocampal neurogenesis. Furthermore, house dust mite-induced dermatitis gave rise to no depressive phenotypes in IL-6-deficient mice. Single-cell RNA sequencing analysis showed high expression of IL-6Rβ, unlike IL-6Rα, in hippocampal cells isolated from NC/Tnd mice. Addition of IL-6 and sIL-6Rα to neuronal progenitor cells cultured from the murine hippocampal dentate gyrus significantly reduced the number of DCX-positive cells, whereas IL-6 alone had no effect. Overall, these findings suggest that increased peripheral blood IL-6 and sIL-6Rα following atopic inflammation inhibits hippocampal immature neurogenesis via IL-6Rβ and is a critical risk factor for the development of mood and behavioral disorders in AD.

Subject terms: Depression, Diagnostic markers, Molecular neuroscience

Introduction

Atopic dermatitis (AD) is a chronic relapsing skin disease, characterized by severe pruritus and eczematous lesions, including hyperkeratosis, parakeratosis, and an increase in the number of resident and infiltrating inflammatory/immune cells such as mast cells, eosinophils, and T cells [1]. Patients with AD often experience significant psychosocial and behavioral problems [2]. Recent reports suggest that children with severe eczema have more difficulty with psychosocial adjustment and exhibit stronger clinginess and fear than unaffected children [3, 4]. AD is also linked to more well-defined psychological disorders, such as depression, attention deficit hyperactivity disorder, and autism [5]. Depression is a major complication of AD (10.1%) as compared to other skin diseases, and current antidepressant therapies are ineffective for these patients [6]. Although clinical evidence suggests that AD is linked to depression, the exact pathogenesis of depression in AD remains unclear. On the other hand, evidence accumulated in human patients and animal models for depression supports a high association between the development of depression and dysregulated neurogenesis in the dentate gyrus of the hippocampus [7].

We hypothesized that immune responses induced in AD are involved in subsequent depression. We used a murine NC/Tnd model for spontaneous AD which we discovered. AD-like skin lesions spontaneously develop in NC/Tnd mice within a couple of wk after weaning under the air-unregulated conventional condition (hereafter conventional mice) but not under the air-regulated specific pathogen free (SPF) condition and the disease profile is very similar to that of human AD [8–10]. Therefore, NC/Tnd mice have been widely used for elucidating the pathogenesis of AD [11–13]. Here we found that conventional NC/Tnd mice with dermatitis, unlike SPF mice without dermatitis, manifested typical depressive symptoms (anxiety, anhedonia, and despair) in depression assessment tests such as the open field test, sucrose preference test, and tail suspension test; as well as decreased neurogenesis in the hippocampus. Several inflammatory cytokines are known to influence the onset and pathogenesis of AD [1, 14]. Molecularly targeted therapies, focusing on the receptors for interleukin (IL)-4/IL-13 [15–17] and IL-31 [18, 19], have been successfully used as new therapies for AD. In this study, we clearly demonstrated that blood IL-6 is an important factor that functionally impairs the hippocampal neurogenesis and triggers depressive symptoms in an atopic mouse model.

Materials and methods

Mice

Conventional NC/Tnd mice with AD and SPF NC/Tnd mice without AD were maintained in the facility of the Tokyo University of Agriculture and Technology as previously described [8–10]. C57BL/6J mice and C3H/HeN mice were purchased from Japan SLC (Shizuoka, Japan). C57BL/6J mice were used as a standard control for the depression model. As NC/Tnd mice have a congenital Rd1 gene mutation in the retina, C3H/HeN mice with the same point mutation were preferred as a blind control. IL-6-deficient mice (B6.129S2-Il6tm1Kopf/J) were supplied by The Jackson Laboratory (Strain # 002650). Congenic IL-6-deficient NC/Tnd mice were generated by backcrossing NC/Tnd mice onto B6.129S2-Il6tm1Kopf/J mice for more than 10 generations. IL-6 deficiency in these mice was confirmed by genotyping and an ELISA. Because NC/Tnd mice have a stop-gain mutation (C to T) at position c.706 of Clec10a, the encoded protein lacks a C-type lection-like domain [20]. NC/Tnd-Clec10ac.706T/C mice restored by the CRISPR-Cas9 system were used [20]. Male mice weighing 20−28 g of several ages were used in all the experiments. Mice were housed in clear acrylic cages and had free access to standard chow and water. The temperature and humidity in the animal room were 22 ± 4 °C and 40 ± 15%, respectively. The animal room was maintained on a 12:12-h light-dark cycle. The allocation to each group was performed randomly by individuals who did not know that each experiment would be used for and in vivo experiments using mice employed groups of six or seven mice to achieve statistical significance (simple-blind method). At the end of each experiment, mice were anesthetized by isoflurane (2−3%) inhalation and then euthanized by cervical dislocation. If their health deteriorated during the experiment period, they were euthanized based on ethical considerations and removed from the data.

Open field test

Each mouse was placed into an open field box (500 W X 500D X 400H mm) equipped with LED lights and photobeam sensor units (Image OFCR for open field test, O’Hara & Co., Ltd., Tokyo, Japan) to quantify locomotor activity and anxiety-like behavior [21]. The time spent in the rearing time, central partition time, and immobility time were measured for 15 min.

Sucrose preference test

The sucrose preference test was performed using a two-bottle choice procedure [22]. The mice were housed individually for 3 days. Four days before the experiment, the mice were continuously exposed to tap water for 24 h. On the test day, the mice were given free access to the two bottles whose weights were measured before the start of the test: one containing tap water and the other containing 1% (wt/vol) sucrose (FUJIFILM Wako Pure Chemical, Osaka, Japan, 196-00015). After 24 h, the bottles positions were changed, and the post-weight of the bottles was measured after next 24 h. Sucrose preference over water (sucrose/water) was quantified by the ratio of the bottle wt.

Tail suspension test

The tail suspension test was performed as described previously [23]. Briefly, the immobility time during the last 4 min of a 6-min testing session was measured as an index of depressive behavior.

Immunohistochemistry

Whole bodies were fixed with 4% paraformaldehyde (FUJIFILM Wako Pure Chemical, 162-16065) under medetomidine (Meiji Seika Pharma, Tokyo, Japan), midazolam (Fuji Pharma, Tokyo, Japan), and butorphanol (Meiji Seika Pharma) mixed anesthetic by the transcardiac perfusion technique as described [24]. Five-μm paraffin-embedded coronal sections of the hippocampus were prepared. To evaluate neurogenesis in the dentate gyrus, immunohistochemical analysis was performed with rabbit anti-doublecortin (DCX) Ab (1:10,000; Abcam, Cambridge, UK, ab18723), rabbit anti-brain lipid binding protein (BLBP) Ab (1:1,000; Abcam, ab32423), and biotinylated goat anti-rabbit IgG H&L Ab (Abcam, ab6720) according to the Abcam protocol with heat-induced epitope retrieval. After adding HRP/Streptavidin (1:1,000; DAKO, 0397), the color was developed by the working solution of DAB EqV Substrate Kit (Vector Laboratories, CA, SK-4103). DCX- and BLBP-positive cells in the left and right dentate gyrus were counted and averaged.

In blood brain barrier (BBB) experiments, sagittal sections (14 μm thick) of frozen brain hemisphere samples were incubated overnight at 4 °C with a mixture of rat anti-CD31 mAb (1:100; Proteintech, IL, Clone 390, 65058-1-Ig) and rabbit anti-occludin mAb (1:200; Cell Signaling Technology, Clone E6B4R, 91131) or rabbit anti-human ZO-1 polyclonal Ab (1:500; Proteintech, 21773-1-AP). To visualize the target cells, sections were treated for 1 h at room temperature with a mixture of donkey anti-rat IgG (H + L) secondary Ab conjugated with Alexa FluorTM 555 (1:1,000; Invitrogen, MA, A78945) and donkey anti-rabbit IgG (H + L) secondary Ab conjugated with Alexa FluorTM 647 (1:1,000; Invitrogen, A31573). As mounting media, ProLongTM gold antifade mountant with DNA stain DAPI (Invitrogen, P36935) was used. Fluorescence images were obtained using a Keyence BZ-X810 fluorescence microscope [TRITC filter for CD31 (Keyence, Osaka, Japan, OP-87764) and Cy5 filter for occludin and ZO-1 (Keyence, OP-87766)].

Evoked-dermatitis model

To WT NC/Tnd-Clec10ac.706T/T, IL-6-deficient NC/Tnd-Clec10ac.706T/T, and NC/Tnd-Clec10ac.706T/C mice, 100 mg of house dust mite (HDM, Dermatophagoides farinae) ointment (BiostirAD, Biostir, Osaka, Japan) was applied to the shaved dorsal skin and both surfaces of each ear evenly at 2 h after pretreatment with 4% SDS; this procedure was repeated twice a wk for 4 wk. One wk after the last application with HDM ointment, clinical parameters and depressive behavioral parameters were assessed, and then skin samples were taken from the back.

Immunocytochemistry

Neuronal progenitor cells (NPCs)/well were fixed with 200 μl of 4% paraformaldehyde phosphate buffer solution (Nacalai Tesque, Kyoto, Japan, 09154-85) for 20 min at room temperature. After washing with PBS twice, the cells were treated with blocking reagent II (Nichirei Bioscience, Tokyo, Japan, 426042) for 1 h. To detect IL-6R on the cell surface, samples were incubated with 100 μl of 1st Ab mixture [rabbit anti-human/mouse IL-6Rα polyclonal Ab (1:300; Invitrogen, PA5102425) and rat anti-mouse gp130 mAb (R&D Systems, Clone 125623, MAB4681)] overnight at 4 °C, followed by 100 μl of 2nd Ab mixture [goat anti-rabbit IgG (H + L) cross-adsorbed secondary Ab conjugated with Alexa FluorTM 594 (1:1,000; Invitrogen, A11012) and goat anti-rat IgG (H + L) cross-adsorbed secondary Ab conjugated with Alexa FluorTM 488 (1:1,000; Invitrogen, A11006)] for 1 h at room temperature in the dark. Fluorescence images were obtained using a Keyence BZ-X810 fluorescence microscope [Texas Red filter for IL-6Rα (Keyence, OP-87765) and Green Fluorescent Protein filter for gp130 (Keyence, OP-87763)].

In another experiment, NPCs (3 ×103 cells) were resuspended in 200 μl of the growth medium without heparin sodium, seeded into a well of poly-D-lysine/laminin coated 8-well chamber slides, and incubated for 48 h at 37 °C in a humidified atmosphere of 5% CO2 and 95% air. Two hundred μl of mouse rIL-6 (100 ng/ml), rIL-6 and soluble IL-6Rα (sIL-6Rα) (100 ng/ml; R&D Systems, 1830-SR), or vehicle was added into the culture medium 48 h later. After fixing with 4% paraformaldehyde, the cells were treated with 300 μl of 0.1% Triton-XTM-100 to perforate the cell membrane according to the manufacturer’s protocol (Cell Signaling Technology, MA). DCX and BLBP were stained using sheep anti-human/mouse DCX polyclonal Ab (1:100; R&D Systems, AF10025)/donkey anti-sheep IgG secondary Ab conjugated with Alexa FlourTM 488 (1:1,000; Invitrogen, A11015), and rabbit anti-BLBP mAb conjugated with Alexa FlourTM 647 (1:300; Abcam, Clone EPR24033-13, ab281734). Fluorescence images were captured using a Keyence BZ-X810 fluorescence microscope [Green Fluorescent Protein filter for DCX (Keyence, OP-87763) and Cy5 filter for BLBP].

Statistical analysis

All data were compared using two-way ANOVA, followed by Tukey’s test, Dunnett’s test, or Mann-Whitney U test, as described in each figure legend and table footnote. P values of less than 0.05 were considered statistically significant. Significance was shown as *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. All animal data are presented as mean ± SEM of at least 3 independent experiments. Plasma cytokine levels are presented as median and interquartile ranges, and differences between groups were determined using Mann-Whitney U test. Analyses were performed using GraphPad Prism 10 software (San Diego, CA).

Study approval

All animal experiments complied with the guidelines of the University Animal Care and Use Committee of the Tokyo University of Agriculture and Technology, as well as with the guidelines of the Science Council of Japan for the use of laboratory animals. All animal experiments were approved by the University Animal Care and Use Committee of the Tokyo University of Agriculture and Technology (No. R03-202, No. R05-151, No. R06-20, and No. R07-39).

Human study was approved by the Ethics Committee of Juntendo University (No. 2017077). The purpose and procedures of this study were explained in detail, and written informed consent was obtained from all participants.

Results

AD patients and conventional NC/Tnd mice with AD exhibit depressive phenotypes

Since a meta-analysis of articles published from 1946 to 2018 reveals a relationship between AD and suicide [25], a small-scale study with 8 patients with moderate to severe AD and 13 healthy subjects was recruited in Juntendo University Urayasu Hospital, Japan (Table S1). AD patients showed higher scores of both 17-items Hamilton Depression Rating Scale (HAM-D17) and Beck Depression Inventory (BDI), which are indicative of depression. The HAM-D17 scores were positively correlated with Visual Analogue Scale (VAS) scores of AD (Fig. S1). To further confirm this phenomenon, an animal model for human AD, the NC/Tnd mouse, was used in this current study. As shown in Fig. 1A, increased clinical skin severity scores were observed in conventional NC/Tnd mice at 9 wk of age, which worsened as the mice aged. In contrast, SPF NC/Tnd mice did not develop eczema. Significant histopathological changes such as thickened epidermis due to hyperplasia with hyperkeratosis, elongation of the rete ridges, and dermal infiltration of numerous eosinophils and mononuclear cells were noted in the dorsal skins of conventional NC/Tnd mice, but not in SPF NC/Tnd mice. In addition, the frequency of scratching, a key symptom of AD, was also increased from 9 to 15 wk of age in conventional NC/Tnd mice compared with that in age-matched SPF NC/Tnd mice (Fig. 1B).

Fig. 1. Conventional NC/Tnd mice with AD-like skin lesions manifest depression-like phenotypes.

Fig. 1

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A, B Clinical skin severity scores and scratching frequency were counted at indicated ages in SPF NC/Tnd mice (blue) and conventional NC/Tnd mice (red) according to the previously reported methods [8, 10]. n = 7 per group. Macro-photographs and H&E-stained specimens of dorsal skin sections obtained at 15 wk of age. Scale bars, 100 μm. C, F Time per 15 min for individual parameters in the open field test for SPF NC/Tnd mice (blue) and conventional NC/Tnd mice (red) at indicated ages, or C57BL/6J mice treated with vehicle and C57BL/6J mice treated with corticosterone. n = 7 per group. E Trace images for 15 min in the open field test for SPF NC/Tnd mice, conventional NC/Tnd mice at 15 wk of age, and C57BL/6J mice treated with corticosterone. n = 7 per group. G, H Sucrose preference values and immobility time per 4 min in the tail suspension test are shown in SPF NC/Tnd mice (blue) and conventional NC/Tnd mice (red) at indicated ages, or C57BL/6J mice treated with vehicle and C57BL/6J mice treated with corticosterone. n = 7 per group. I, J Number of DCX-positive or BLBP-positive cells in immunohistochemically stained specimens of hippocampus sections obtained from SPF NC/Tnd mice (blue) and conventional NC/Tnd mice (red) at indicated ages, or C57BL/6J mice treated with vehicle and C57BL/6J mice treated with corticosterone. DCX-stained specimens of hippocampus sections obtained at 15 wk of age. Scale bars, 100 μm (inset, 20 μm). A, E, I Results are representative of 3 independent experiments. (A−D, F−J) Results are shown as mean ± SEM of values determined from 3 independent experiments. Dunnett’s multiple comparisons test and Mann-Whitney U test.

To examine whether conventional NC/Tnd mice developed a depressive phenotype (reduced general locomotor activity, anxiety behavior, impaired preference, and learned helplessness), we conducted three different behavioral tests: an open field test, a sucrose preference test, and a tail suspension test. First, mice were placed in an open field to evaluate exploratory- and anxiety-related behaviors. Rearing time, central partition time, and immobility time were quantified for 15 min. We found that rearing time and central partition time were markedly reduced (Fig. 1, D), and immobility time clearly prolonged (Fig. 1F) in conventional NC/Tnd mice from 9 wk of age, comparable to C57BL/6J mice treated with corticosterone in a depression model [26]. As shown in Fig. 1E, the tracking trajectory revealed that mice with AD (9 wk of age) generally congregated at the edge of the open field compared with SPF NC/Tnd mice. Second, a sucrose preference test was performed using a two-bottle choice method. Mice were given free access to two bottles (one containing tap water, and another containing 1% sucrose), and the percentage of 1% sucrose intake was calculated. Conventional NC/Tnd mice from 9 wk of age were compared with a corticosterone-treated positive control, and showed that the sucrose preference was clearly impaired (Fig. 1G). Third, despair-related behavior was assessed by a tail suspension test. Immobility time was prolonged in conventional NC/Tnd mice from 9 wk of age comparable with C57BL/6J mice treated with corticosterone (Fig. 1H), whereas SPF NC/Tnd mice were maintained within the normal range during the study period. C3H/HeN mice were used as a visually impaired control, which carried the same point mutation in the retina as NC/Tnd mice [27], but displayed neither skin lesions nor depression-like symptoms in the same conventional circumstance (Fig. S2).

NC/Tnd mice with skin lesions exhibit disturbances in hippocampal neurogenesis

As chronic inflammation-induced disruption of hippocampal neurogenesis is thought to cause behavioral problems [28], we studied the expression of neural differentiation markers such as BLBP for neuronal progenitors and DCX for immature neurons in the hippocampal dentate gyrus [29]. Surprisingly, DCX-positive cells rapidly declined in conventional NC/Tnd mice at 9 wk of age as compared with those in C57BL/6J mice treated with corticosterone (Fig. 1I). Moreover, the number of BLBP-positive cells did not change in conventional NC/Tnd mice even after the onset of skin lesions, whereas a significant decrease was noted in C57BL/6J mice treated with corticosterone (Fig. 1J). Thus, we concluded that conventional NC/Tnd mice with eczema manifested marked depression-like behavior and the decreased number of DCX-positive cells in the hippocampal dentate gyrus.

Depression-inducing substance(s) is present in the circulating blood of NC/Tnd mice with skin lesions

We next conducted two experiments to determine whether factors in the blood of the NC/Tnd mice triggered the disruption of neurogenesis in the hippocampal dentate gyrus via the peripheral blood. First, sera obtained from 9-wk-old conventional NC/Tnd mice or age-matched SPF NC/Tnd mice were i.v. transferred to 6-wk-old SPF NC/Tnd mice twice a week for 8 wk. As shown in Fig. 2A, reduced numbers of DCX-positive immature cells, but not BLBP-positive progenitors, were found in the hippocampal dentate gyrus of mice repeatedly injected with sera obtained from conventional mice with severe dermatitis. The injection with sera obtained from SPF mice without dermatitis had no effect on the mice. In addition, parabiosis was also performed with SPF-SPF, SPF-Conventional, and Conventional-Conventional pairs. We found that in SPF mice paired with conventional mice, a decrease in the number of DCX-positive cells was noted when compared with that in SPF-SPF pairs (Fig. 2B). However, there was no difference in the number of BLBP-positive cells between the groups. We hypothesized that inflammatory mediator(s) produced by atopic skin lesions and released into the circulation may cause depressive symptoms in the affected NC/Tnd mice.

Fig. 2. Peripheral blood IL-6 leads to the development of depression-like phenotypes.

Fig. 2

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A Number of DCX-positive or BLBP-positive cells in immunohistochemically stained specimens of hippocampus sections obtained from SPF NC/Tnd mice repeatedly injected with sera obtained from 9-wk-old SPF NC/Tnd mice or conventional NC/Tnd mice. n = 6 per group. B Number of DCX-positive or BLBP-positive cells in immunohistochemically stained specimens of hippocampus sections obtained from SPF-SPF, SPF-Conventional, and Conventional-Conventional parabiotic pairs. n = 7 per group. C Cytokine levels in the plasma collected from 9-wk-old SPF NC/Tnd mice and conventional NC/Tnd mice. n = 7 per group. Results are shown using a box plot that is composed of the median (solid line in each column), upper hinge, lower hinge, and whiskers representing upper adjacent value or lower adjacent value determined from 3 independent experiments. D Clinical skin severity scores and scratching frequency were measured at indicated timepoints in conventional NC/Tnd mice injected with control mouse IgG1, anti-IL4Rα mAb, or anti-IL-6 mAb twice a wk for 4 wk. n = 7 per group. E Time per 15 min for individual parameters in the open field test for conventional NC/Tnd mice 1 wk after the last injection. n = 7 per group. F, G Sucrose preference values and immobility time per 4 min in the tail suspension test are shown for NC/Tnd mice 1 wk after the last injection. n = 7 per group. (H) Number of DCX-positive or BLBP-positive cells in immunohistochemically stained specimens of hippocampal sections obtained from NC/Tnd mice after completing the depressive symptom assessment tests. n = 7 per group. A, D−H Results are shown as mean ± SEM of values determined from 3 or 4 independent experiments. A, C Mann-Whitney U test. B Two-way ANOVA using Tukey’s multiple comparisons test. D−H Dunnett’s multiple comparisons test.

Peripheral blood IL-6 is strongly correlated with the development of depressive symptoms accompanied by skin lesions

To explore depression trigger(s) in the peripheral blood, relevant cytokines were quantified by using a multiplex assay. There were no differences in the plasma levels of all cytokines between 6-wk-old SPF and conventional NC/Tnd mice; however, at 9 wk of age, the levels of IL-4, IL-6, IL-13, and sIL-6Rα were significantly higher in conventional NC/Tnd mice compared with SPF NC/Tnd mice (Fig. 2C). At 15 wk of age, plasma levels of several cytokines such as IL-4, IL-12p70, IL-33, C-C motif chemokine ligand 2 (CCL2), IFN-γ, TNF-α, and thymic stromal lymphopoietin (TSLP) were significantly elevated in conventional NC/Tnd mice (Fig. S3A). Conventional NC/Tnd mice manifested depressive behavior and the decreased number of DCX-positive cells in the dentate gyrus at as early as 9 wk of age, suggesting the possible involvement of IL-4, IL-13, or IL-6/sIL-6Rα in the development of depressive symptoms. Therefore, the optimal doses of these cytokines, calculated based on previous studies [30–32], were injected into SPF NC/Tnd mice once daily for 4 wk. Repeated injections with a mixture of rIL-4 and rIL-13 did not cause either dermatitis (Fig. S4A) or depressive symptoms (Fig. S4B−D). On the other hand, repeated injections with rIL-6 induced depressive symptoms (Fig. S4B−D) and the decreased number of DCX-positive cells in the hippocampal dentate gyrus (Fig. S4E), but not dermatitis. In AD patients, plasma levels of IL-4 and IL-6 were significantly higher than in healthy subjects (Fig. S3B).

In a related set of experiments, anti-IL-4Rα neutralizing mAb or anti-IL-6 neutralizing mAb was injected into conventional NC/Tnd mice twice a wk for 4 wk. Administration of anti-IL-4Rα mAb significantly suppressed the development of dermatitis and the scratching frequency (Fig. 2D), but had only a marginal effect on the development of depressive behavior and no effect on the number of DCX-positive cells in the dentate gyrus (Fig. 2E−H). In contrast, mice injected with anti-IL-6 mAb did not change the severity of dermatitis (Fig. 2D), but their depressive symptoms improved and the number of DCX-positive cells returned to normal levels (Fig. 2E−H).

To further confirm the involvement of these cytokines, we treated 6-wk-old conventional NC/Tnd mice with either a Janus kinase (JAK) inhibitor for IL-4R, baricitinib, or a gp130 (IL-6Rβ) inhibitor, SC144 hydrochloride for 4 wk. Baricitinib, unlike SC144, reduced the skin severity scores and scratching frequency (Fig. S5A). In contrast, only SC144 led to improvement in depressive symptoms (anxiety, anhedonia, and despair) and increased the number of DCX-positive cells in the dentate gyrus (Fig. S5B−E). Thus, we concluded that peripheral blood IL-6 was a key depression-inducing factor in conventional NC/Tnd mice suffering from AD-like skin lesions.

Using IL-6-deficient NC/Tnd-Clec10ac.706T/T mice, we further demonstrated that repeated application with HDM ointment led to high clinical skin severity and scratching frequency 1 wk after the last application compared with WT NC/Tnd-Clec10ac.706T/T mice (Fig. 3A); however, all parameters of depressive behavior (Fig. 3B−D) and the numbers of DCX-positive cells and BLBP-positive cells were comparable with those of control mice treated with SDS alone (Fig. 3E).

Fig. 3. HDM-induced dermatitis does not induce depressive phenotypes in IL-6-deficient NC/Tnd-Clec10ac.706T/T mice or gene-restored NC/Tnd-Clec10ac.706T/C mice.

Fig. 3

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WT NC/Tnd-Clec10ac.706T/T mice, IL-6-deficient NC/Tnd-Clec10ac.706T/T mice, and gene-restored NC/Tnd-Clec10ac.706T/C mice were repeatedly challenged with SDS alone or HDM ointment twice a wk for 4 wk, and 1 wk after the last application, all parameters were assessed. A Clinical skin severity scores and scratching frequency were calculated. H&E-stained specimens of dorsal skin sections obtained after completing the depressive symptom assessment tests. Scale bars, 100 μm n = 7 per group. B Time per 15 min for individual parameters in the open field test. n = 7 per group. C, D Sucrose preference values and immobility time per 4 min in the tail suspension test. n = 7 per group. E Number of DCX-positive or BLBP-positive cells in immunohistochemically stained sections of hippocampus sections obtained from mice after completing the depressive symptom assessment tests. n = 7 per group. F IL-6 levels in the plasma collected from NC/Tnd mice. n = 7 per group. Results are shown using a box plot that is composed of the median (solid line in each column), upper hinge, lower hinge, and whiskers representing upper adjacent value or lower adjacent value determined from 3 independent experiments. A−E Results are shown as mean ± SEM of values determined from 3 independent experiments. Mann-Whitney U test. F Two-way ANOVA using Tukey’s multiple comparisons test.

The HDM ointment was applied to gene-restored NC/Tnd-Clec10ac.706T/C mice, which have a binding site for the mucin-like molecule in the HDM (the ligand for Clec10a) that induces an inhibitory signal for proinflammatory cytokines including IL-6. Mild AD-like skin lesions were observed, but the mice did not develop depressive symptoms (Fig. 3A−E). At that time, blood IL-6 levels were very low and comparable to WT NC/Tnd-Clec10ac.706T/T mice treated with SDS alone (Fig. 3F).

Both NPCs and neuroblasts (NBs) express Il6st

To identify IL-6R-positive cell types in the hippocampus tissue of SPF NC/Tnd mice, single-cell RNA sequencing (scRNA-seq) analysis of isolated hippocampal cells was conducted. As shown in Fig. 4A and Fig. S6A, in the uniform manifold approximation and projection (UMAP) plot, various cell clusters were successfully classified based on their characteristic mRNA expression [33–35]. Among these cell clusters, Dcx-positive cells were found predominantly in interneurons, subiculum-neurons, subiculum-entorhinal neurons, and neurogenic lineage; and Fabp7 (BLBP gene)-positive cells were observed in astrocytes and NPCs (Fig. 4B). As for IL-6R, Il6ra was expressed only in cells composed of the microglial clusters. In contrast, Il6st (IL-6Rβ gene) expression was relatively widespread in the hippocampal component clusters (Fig. 4B). Focusing on the neuronal differentiation cluster, Dcx mRNA was expressed in about 50% of NBs and in 25% of NPCs, whereas Fabp7-positive cells were specific for the NPC cluster (Fig. 4C−E; and Fig. S6B). The percentage of Il6ra-positive cells was less than 1% in three different stages of cell groups. In contrast, the percentage of Il6st-positive cells was about 10% in NPCs and 18% in NBs (Fig. 4E).

Fig. 4. Il6st is expressed in both NPCs and NBs of hippocampal cells obtained from SPF NC/Tnd mice.

Fig. 4

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A UMAP from a total of 71, 837 hippocampal cells. B Expression of selected genes (Dcx, Fabp7, Il6ra, or Il6st) overlaid on the UMAP A. C UMAP of subclusters derived from the neurogenic lineage. D Expression of selected genes (Dcx, Fabp7, Il6ra, or Il6st) overlaid on the UMAP C. E Proportion of selected gene-positive cells (Dcx, Fabp7, Il6ra, or Il6st) in individual subclusters.

IL-6 impairs BBB permeability

Next, we assessed the BBB permeability in this mouse model. Considering the mol wt of IL-6, FITC-conjugated 20 kD dextran was injected i.p. into 9-wk-old conventional NC/Tnd mice and aged-matched non-treated SPF NC/Tnd mice. Fifteen min later, the permeability index (PI) of the brain was calculated. The PI values were significantly higher in conventional NC/Tnd mice than in SPF NC/Tnd mice (Fig. 5A). To examine the possible direct effect of IL-6/sIL-6Rα on BBB permeability, rIL-6/IL-6Rα protein chimeras (50 ng/g body wt) were injected into SPF NC/Tnd mice. Six h later, FITC-conjugated dextran was injected. Higher PI values were detected in mice injected with the rIL-6/IL-6Rα protein chimera (Fig. 5A). In addition, reduced expression of occludin and ZO-1 was observed in the brains of conventional mice and mice treated with IL-6/sIL-6Rα (Fig. 5B). Thus, we concluded that IL-6/sIL-6Rα impaired the BBB permeability in NC/Tnd mice via a reduction of tight junction molecules, allowing FITC-conjugated dextran to transfer from the blood to the brain.

Fig. 5. IL-6 enhances the BBB permeability and suppresses differentiation of NPCs.

Fig. 5

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A The PI calculated from FITC activity in the brain and the peripheral blood of 9-wk-old SPF NC/Tnd mice i.p. injected with/without rIL-6/IL-6Rα protein chimera (50 ng/g body wt) or vehicle. Conventional NC/Tnd mice at 9 wk old were used as a positive control. n = 6 per group. B The brain samples at 9-wk-old mice were co-stained with CD31 and occludin or ZO-1. Scale bars, 50 μm. C IL-6R-positive cells in immunocytochemically stained specimens of NPCs originated from murine hippocampal dentate gyrus tissues. Scale bars, 100 μm and 20 μm (inset). D NPCs cultured with rIL-6 alone (100 ng/ml), rIL-6 and sIL-6Rα (100 ng/ml), or control vehicle for 48 h were stained for BLBP and DCX. Scale bars, 200 μm and 50 μm (inset). A Results are shown as mean ± SEM of values determined from 3 independent experiments. Dunnett’s multiple comparisons test. B−D Results are representative of 3 independent experiments.

IL-6 suppresses the differentiation of NPCs

Finally, we examined whether IL-6 directly affected hippocampal neurogenesis using an in vitro model of NPCs derived from the hippocampal dentate gyrus of SPF NC/Tnd mice. Interestingly, most NPCs immunocytochemically expressed IL-6Rβ on the cell surface, but not membrane-bound IL-6Rα (mIL-6Rα) (Fig. 5C). After NPCs were cultured for 48 h, rIL-6 (100 ng/ml), a mixture of rIL-6 (100 ng/ml) and sIL-6Rα (100 ng/ml), or control vehicle was added to the culture medium and the culture was continued for 48 h. NPCs treated with rIL-6 alone showed low expression of BLBP and high expression of DCX, comparable to control vehicle (Fig. 5D). In contrast, treatment with a mixture of rIL-6 (100 ng/ml) and sIL-6Rα (100 ng/ml) induced high expression of BLBP and low expression of DCX (Fig. 5D). In addition, rIL-6 and sIL-6Rα did not affect total cell counts, viability, or proliferation of NPCs (Fig. S7). Thus, we concluded that the rIL-6/sIL-6Rα complex suppressed neurogenesis from progenitors to immature neurons via IL-6Rβ.

Discussion

Previous cohort studies have reported that AD patients have a higher prevalence of depression and/or suicide than non-AD subjects in USA, European countries, and Asian countries [36]. We have confirmed significantly higher scores of HAM-D17 and BDI in both male and female AD patients in the small-scale study. The mechanism underlying this association was previously unknown. To clarify the pathogenesis of AD-associated depression, an animal model for human AD is extremely useful. Our results clearly demonstrated that NC/Tnd mice with spontaneous AD-like skin lesions, an animal model for human AD, exhibited indicators of depressive behavior at the onset of AD development at 9 wk of age. Repeated application with HDM to SPF NC/Tnd mice induced severe skin lesions and subsequently depressive behavior, suggesting that AD-like dermatitis may be causally related to the initiation of depressive symptoms in NC/Tnd mice.

In the dentate gyrus of conventional NC/Tnd mice, the number of DCX-positive immature cells was reduced, but the number of BLBP-positive progenitor cells was unchanged, suggesting that depressive behavior triggered by AD-like skin lesions in this model may be due to impairment of neural maturation from neural progenitors to immature neurons in the hippocampal dentate gyrus. Immunohistopathological observations support this hypothesis [37]. In patients with AD, elevated levels of various inflammatory cytokines have been detected in the peripheral blood [38, 39]. Therefore, we focused on peripheral blood cytokines and their possible involvement in the development of depressive symptoms in our atopic mice. First, the transfer of sera from the conventional mice to the SPF mice and parabiosis between the conventional mice and the SPF mice resulted in a reduction in the number of DCX-positive immature cells in the SPF mice. Second, high blood levels of IL-6, but not of IL-4 or IL-13, were associated with depressive behavior. Third, administration of IL-6 impaired neurogenesis, even though no dermatitis appeared. Fourth, HDM, which can induce AD, elicited depressive behavior in SPF IL-6-sufficient mice, but not in IL-6-deficient mice. These results clearly demonstrated that elevated IL-6 in the peripheral blood directly causes depressive symptoms in NC/Tnd mice.

IL-6 is a pleiotropic proinflammatory cytokine with a wide range of biological effects that is released by immune and non-immune cells involved in AD, including T cells [40], macrophages [41], mast cells [42], keratinocytes [43], and fibroblasts [44], leading to increased concentrations in the peripheral blood of animal models [45] and patients [46]. It exhibits biological activities through two distinct signaling cascades [47]. IL-6 binds to mL-6Rα and subsequently dimerizes IL-6Rβ (gp130). Trans-signaling may also occur, in which a complex of IL-6 and sIL-6Rα binds to IL-6Rβ. The latter signaling functions on various types of remote cells which express only IL-6Rβ, such as neurons. Indeed, scRNA-seq analysis of hippocampal cells showed that Il6st was widely expressed in constitutive clusters, including vascular endothelial cells, while Il6ra was expressed only in microglial clusters; and that Il6st-positive subclusters were detected in the neurogenic lineage cluster. Furthermore, hippocampus-derived NPCs were immunocytochemically positive only for IL-6Rβ. The addition of both rIL-6 and sIL-6Rα, but not rIL-6 alone, induced high expression of BLBP and low expression of DCX, indicating that the differentiation from IL-6Rβ-positive progenitors to immature neurons was inhibited primarily through the trans-signaling process of IL-6. Decreased hippocampal neurogenesis is thought to be involved in the development of depressive behavior [48, 49]. IL-6 enhances BBB permeability in human in vitro and ex vivo models [50] and murine in vivo models [51], and is thus transferred across the BBB from the peripheral blood to the brain in mice injected i.v. with IL-6 [52, 53]. In this study, treatment with IL-6 increased permeability of the BBB via reduced tight junction molecules in the brain of SPF NC/Tnd mice without skin lesions and vascular endothelial cells in the hippocampal tissue showed high expression of Il6st, confirming that the BBB was impaired by IL-6 in atopic mice. Therefore, a complex of IL-6 and sIL-6Rα that penetrated from the peripheral blood to the brain through the impaired BBB could directly inhibit neurogenesis in the hippocampal dentate gyrus, resulting in depression-like behavior at the early stage of AD-like skin lesions in atopic mice (Fig. 6).

Fig. 6. Increased blood levels of IL-6 and sIL-6Rα at the initiation stage of AD promote the BBB permeability and subsequently inhibit neurogenesis in the hippocampus, leading to depressive symptoms in atopic mice.

Fig. 6

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HDM-derived components (MLM and TLRL) activate keratinocytes, immunocompetent cells, and fibroblasts. TLRLs such as TLR4 bind to their specific receptors expressed on these cells and stimulate the production of inflammatory cytokines such as IL-6. MLMs, on the other hand, bind to the C-type lectin receptor, Clec 10a and inhibit their cytokine-producing signals. Because WT NC/Tnd-Clec10ac.706T/T mice lack CTLD, the inhibitory signals for cytokine production do not work well [20]. As a result, large amounts of IL-6 and sIL-6Rα are produced in atopic skin lesions and their levels in the peripheral blood are high. The IL-6 and sIL-6Rα conjugate binds to IL-6Rβ of the BBB endothelium, increasing the permeability of the BBB, and this conjugate passes through the BBB, binds to IL-6Rβ expressed on NPCs and NBs in the hippocampal dentate gyrus, and inhibits neurogenesis. This sequence of events with IL-6 results in the development of depression-like symptoms in WT NC/Tnd mice. CTLD, C-type lectin-like domain; Fb, fibroblast; MC, mast cell; MΦ, macrophage; MLM, mucin-like molecule; NB, neuroblast; NPC, neuronal progenitor cell; NSC, neural stem cell; TLRL, TLR ligand.

To examine the possible involvement of circulating IL-6 in the development of AD, tocilizumab (IL-6R blocker) was administered to three AD patients. However, the therapeutic effect of tocilizumab was limited and included unexpected adverse effects [54]. In the present study, non-consecutive administration of the anti-IL-6 neutralizing mAb or the IL-6Rβ inhibitor SC144 showed a slight inhibitory trend against dermatitis, while completely suppressed depressive symptoms. It is well known that IL-6-induced signal transduction activates the JAK/signal transducers and activators of transcription (STAT) 3 via phosphorylation of IL-6Rβ [55]. SC144 induces gp130 phosphorylation (S782) and deglycosylation, and suppresses IL-6-mediated JAK/STAT3 signal transduction, eventually leading to inhibition of the biological actions by IL-6 [56]. SC144 treatment increased the number of DCX-positive cells in the dentate gyrus, suggesting that the effects of IL-6 on NPCs are mediated via the JAK/STAT3 signaling. On the other hand, anti-IL-4Rα mAb or the JAK inhibitor baricitinib almost completely suppressed dermatitis, but had only a marginal effect on depressive symptoms, confirming clinical trials with dupilumab [16]. Thus, long-term IL-4R blocking therapy is not only highly effective in treating AD but also attenuates IL-6 production, which in turn is postulated to reduce secondary depressive symptoms [57].

It is well established that inflammatory cytokines can activate the hypothalamic-pituitary-adrenal axis, leading to release of glucocorticoids which affect NPCs. Psychiatric side effects such as depression [58] and memory deficits [59] have been reported in patients treated with prolonged or high doses of glucocorticoids. In the present study, the administration with corticosterone induced depressive behavior and reduced the number of BLBP-positive NPCs in the hippocampal dentate gyrus. The number of NPCs was not reduced in conventional NC/Tnd mice or SPF NC/Tnd mice treated with IL-6, suggesting that there was no effect on NPCs via the hypothalamic-pituitary-adrenal axis. In clinical practice, the use of systemic glucocorticoids in the treatment of AD [60, 61] and other chronic inflammatory diseases [62, 63] in which IL-6 is produced, has raised concerns that it may exacerbate depression.

HDM antigens are allergenic and known to flare AD. Recently, we found that WT NC/Tnd mice have a stop-gain mutation in Clec10a (Clec10ac.706T/T), and the encoded mutant Clec10a (MGL1/CD301a) lacks a binding site for the mucin-like molecule in HDM, the ligand for Clec10a in dermal macrophages and dendritic cells [20]. In the gene-restored NC/Tnd-Clec10ac.706T/C mice, skin lesions were not only reduced but also HDM-induced proinflammatory cytokine production, including IL-6, in dermal macrophages via TLR4 was suppressed by the Clec10a-mediated negative feedback signal [20]. In the present study using NC/Tnd-Clec10ac.706T/C mice, although repeated application with HDM induced moderate dermatitis, the skin lesions were improved, relating to lower depressive symptoms 1 wk after the last administration. Plasma levels of IL-6 were also lower at the time, suggesting that the Clec10a signaling is critical for suppressing the onset of depression in HDM-induced dermatitis. Hence, some patients with AD may carry mutations in asialoglycoprotein receptor 1 (functional homolog of Clec10a) [64–69] that are involved in the development of depression secondary to AD, but more detailed studies are needed to elucidate this mechanism (Fig. 6).

In summary, this study clearly demonstrated the seminal role of IL-6 in inducing depressive behavior associated with skin lesions in this murine model of AD. We also showed IL-6 has the ability to impair the BBB and neurogenesis in the hippocampus. The results implicate a role of IL-6 antagonists in the treatment of serious mental health problems associated with AD, as well as other inflammatory diseases and illnesses, such as chronic fatigue syndrome and long COVID-19 syndrome.

Supplementary information

Supplementary Materials (39.7KB, docx)
Supplementary Figure 1 (68.2KB, pdf)
Supplementary Figure 2 (115.5KB, pdf)
Supplementary Figure 3 (313.4KB, pdf)
Supplementary Figure 4 (143.5KB, pdf)
Supplementary Figure 5 (165.3KB, pdf)
Supplementary Figure 6 (1.3MB, pdf)
Supplementary Figure 7 (1.6MB, pdf)
Supplementary Table 1 (66KB, pdf)

Acknowledgements

We thank M. Nagasaki (Tokyo University of Agriculture and Technology) for her special animal care and excellent cytokine quantitative analysis. This work was supported by grants from Grant-in-Aid for Scientific Research (S) #16H06383 (to H. Matsuda) and (A) #15H02478 and #19H00969 (to A. Tanaka), provided by the Japan Society for the Promotion of Science, Japan, from Strategic Research Foundation Grant-aided Project for Private Universities #S1311011 (to M. Tominaga and K. Takamori) provided by the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by funding #SGZ-2020-13357 (to H. Matsuda) from Sanofi and Regeneron. P. D. Arkwright and J. L. Pennock are funded by MRC UK (Project Grant MR/W001454/1) and the Leo Foundation (Project Grant No. LF-OC-19-000165).

Author contributions

K. Matsuda, R. Muko, A. Tanaka, C. Moon, and T. Shin performed the experiments and evaluated data. K. Matsuda and H. Matsuda applied statistical analysis. A. Shibuya contributed to experiments with NC/Tnd-Clec10ac.706T/C mice. S. Endo and S. Yanai provided the techniques to administer the depression assessment test and evaluated the data as experts. K. Matsuda and R. Muko maintained mice and collected blood samples. M. Oikawa supported immunohistochemical analysis. M. Tominaga and K. Takamori performed clinical study at the outpatient clinic of Juntendo University Urayasu Hospital. K. Matsuda wrote the draft. P.D. Arkwright, J.L. Pennock, and E. Jensen-Jarolim extensively reviewed and revised the paper. H. Matsuda and A. Tanaka conceived and designed the study, checked all the data obtained, and directed the smooth execution of the project. All the authors had the opportunity to discuss the results and comment on the manuscript.

Data availability

The scRNA-seq analysis data are open in NCBI Gene Expression Omnibus (GEO) records (Accession Number: GSE318233). The data that support the findings of this study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Akane Tanaka, Email: akane@cc.tuat.ac.jp.

Hiroshi Matsuda, Email: hiro@cc.tuat.ac.jp.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41398-026-04211-2.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The scRNA-seq analysis data are open in NCBI Gene Expression Omnibus (GEO) records (Accession Number: GSE318233). The data that support the findings of this study are available from the corresponding author upon reasonable request.

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