2026 ECNP Congress

PS03-3108

Brain-immune system interactions in major depression: role of β2-adrenergic receptor in myeloid and lymphoid cells

Itxasne Berasategui Garro — A. Garayo Larrea, P. Fructos, M.S. Vargas, S. Lizaso, R. Fernandez Ovejero, E. Aubá, F. Ortuño, P. Molero, M.A. Abellanas, R. Tordera · University of Navarra, Pharmaceutical Sciences, Pamplona, Spain

2026 ECNP Congress

Background

Depression has been linked to sympathetic activity, inflammatory responses, and immune system imbalance, illustrating the bidirectional interconnection between mental health and immune function. These interactions can be readily observed in hematopoietic stem cells (HSCs), which are needed for immune homeostasis and are tightly regulated by sympathetic signaling. A recent study showed chronic stress alters bone marrow HSC function, promoting abnormal myeloid cell production, inflammation, and immune gene dysregulation [1]. It is well known that the β2-adrenergic receptor (ADRB2) is highly present in monocytes and T lymphocytes. Its activation by adrenaline and noradrenaline typically results in immunosuppression, including reduced cytokine expression via the cAMP-PKA pathway and other non-traditional pathways [2]. In addition, postmortem studies reported increased β-adrenoceptor expression in the prefrontal cortex (PFC) of suicide victims with major depression (MD) [3]. Moreover, chronic antidepressant treatment has been shown to reduce β-adrenergic receptor expression in the rat brain [4]. Together, these observations suggest that altered adrenergic signalling may play a key role in MD pathogenesis. Therefore, the present work hypothesizes that increased ADRB2 expression in immune cells may represent a compensatory mechanism that counters inflammatory processes, leading to antidepressant-like effects in MD.

Objectives

This project aims to investigate β2-adrenergic receptor expression in immune cells to better characterize neuroimmune interactions in major depressive disorder (MDD), assessing its association with inflammation and treatment response. In addition, we aim to study potential alterations linked to illness or clinical response upstream in undifferentiated hematopoietic progenitors.

Methods

Moderate and severe MD patients diagnosed according to the Montgomery–Åsberg Depression Rating Scale (MADRS >20) were recruited by psychiatrists from several hospitals. Blood samples were collected at baseline (T1) and follow-up after treatment (antidepressants, esketamine, or electroconvulsive therapy) (T2). From these samples, monocyte subsets (CD14+; CD16-/CD14+; CD16+) and T-lymphocytes (CD3+) were isolated by flow cytometry sorting from peripheral blood mononuclear cells (PBMCs). Gene expression analyses (Adrb2, Adra2b, and Il6) were performed for each cell sorted type by real-time quantitative PCR (RT-qPCR). Statistical analyses were performed using two-way ANOVA, followed by appropriate post hoc multiple-comparison tests. In parallel, RNA sequencing (RNA-seq) was performed on hematopoietic progenitors (CD34+) from a small group of MD patients and healthy controls (HC). The study was conducted in accordance with approved ethical protocol. Additionally, secondary analysis of publicly available scRNA-seq data from chronic unpredictable mild stress (CUMS)-exposed mice revealed reduced beta-adrenergic signaling in myeloid cells, suggesting a diminished activation state compared to control animals.

Results

MD patients revealed a significant increase in ADRB2 mRNA expression in classic monocytes compared with HC (p< 0.001), with high levels in both moderate and severe patients. In parallel, increased IL6 mRNA expression was observed in classical monocytes (p < 0.01), particularly in patients with moderate depression. Longitudinal analyses showed that IL6 mRNA levels decreased in responder patients at follow-up compared to baseline (p = 0.025).

Conclusions

These findings support that ADRB2 upregulation may constitute a compensatory mechanism to counteract inflammation and promote resilience to chronic stress, highlighting this pathway as a potential therapeutic target for immune-mediated depressive disorders.

References

  1. Mou, R., Ma, J., Ju, X., Wu, Y., Chen, Q., Li, J., Shang, T., Chen, S., Yang, Y., Li, Y., Lv, K., Chen, X., Zhang, Q., Liang, T., Feng, Y., Lu, X., 2024. Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice. Cell Stem Cell 31(12), 1794–1812.e10.
  2. Chhatar, S., Lal, G., 2021. Role of adrenergic receptor signalling in neuroimmune communication. Curr. Res. Immunol. 2, 202–217.
  3. Rivero, G., Gabilondo, A.M., García-Sevilla, J.A., La Harpe, R., Callado, L.F., Meana, J.J., 2014. Increased α2- and β1-adrenoceptor densities in postmortem brain of subjects with depression: Differential effect of antidepressant treatment. J. Affect. Disord. 167, 343–350.
  4. Manji, H., Brown, J.H., 1987. The antidepressant effect of beta-adrenoreceptor subsensitivity: a brief review and clinical implications. Can. J. Psychiatry 32(9), 788–797.