Stress-experienced monocytes/macrophages lose anti-inflammatory function via β2-adrenergic receptor in skin allergic inflammation

Abstract

Background: Psychological stress can exacerbate the development of allergies; however, the underlying mechanisms remain poorly understood. IgE-mediated cutaneous allergic inflammation (IgE-CAI) is a basophil-dependent skin allergy with eosinophil infiltration at inflammatory sites. Its resolution involves anti-inflammatory programmed death ligand 2 (PD-L2)-positive macrophages.

Objective: This study sought to elucidate the cellular and molecular mechanisms by which psychological stress exacerbates IgE-CAI.

Methods: Neural tissue involved in stress-induced IgE-CAI exacerbation was identified by performing denervation and brain destruction experiments in mice. Immune cell transplantation, RNA sequencing, flow cytometry, and ELISA were used to identify and characterize immune cells with stress-altered functioning, followed by identification of key factors involved in IgE-CAI exacerbation.

Results: Stress-induced exacerbation of IgE-CAI was found to be sympathetic and β₂-adrenergic receptor (Adrb2)-dependent. Adoptive transfer experiments revealed that stress diminished the anti-inflammatory functions of PD-L2-positive macrophages through Adrb2, exacerbating the inflammation. RNA sequencing analysis indicated that PD-L2-positive macrophages in stressed mice exhibit reduced expression of efferocytosis-related genes, including Gas6 and MerTK. Consequently, the efferocytic capacity of these macrophages decreased, resulting in increased numbers of dead cells in the lesions. The exacerbation and upregulation of Ccl24 expression in IgE-CAI skin lesions were countered by a Caspase-1 inhibitor.

Conclusions: Psychological stress diminishes the efferocytotic capacity of PD-L2-positive macrophages, causing an accumulation of dead cells. This, in turn, heightens eosinophil infiltration through Caspase-1-dependent production of CCL24, exacerbating IgE-CAI.

Keywords: Adrb2; Psychological stress; anti-inflammatory macrophage; basophil; efferocytosis; eosinophil; skin allergic inflammation; sympathetic nerve.