Endogenously produced catecholamines improve the regulatory function of TLR9-activated B cells.

Nadine Honke,Matthias Schneider,Georg Pongratz,Alexander Lautwein,Namir Shaabani,Birgit Opgenoorth,John R Teijaro,Torsten Lowin,Takeshi Tsubata

doi:10.1371/journal.pbio.3001513

Abstract

The sympathetic nervous system (SNS) contributes to immune balance by promoting anti-inflammatory B cells. However, whether B cells possess a self-regulating mechanism by which they modulate regulatory B cell (Breg) function is not well understood. In this study, we investigated the ability of B cells to synthesize their own catecholamines upon stimulation with different B cell activators and found that expression of the enzyme tyrosine hydroxylase (TH), required to generate catecholamines, is up-regulated by Toll-like receptor (TLR)9. This TLR9-dependent expression of TH correlated with up-regulation of adrenergic receptors (ADRs), enhanced interleukin (IL)-10 production, and overexpression of the co-inhibitory ligands programmed death ligand 1 (PD-L1) and Fas ligand (FasL). Moreover, concomitant stimulation of ß1-3-ADRs together with a B cell receptor (BCR)/TLR9 stimulus clearly enhances the anti-inflammatory potential of Bregs to suppress CD4 T cells, a crucial population in the pathogenesis of autoimmune diseases, like rheumatoid arthritis (RA). Furthermore, TH up-regulation was also demonstrated in B cells during the course of collagen-induced arthritis (CIA), a mouse model for the investigation of RA. In conclusion, our data show that B cells possess an autonomous mechanism to modulate their regulatory function in an autocrine and/or paracrine manner. These findings help to better understand the function of B cells in the regulation of autoimmune diseases and the interplay of SNS.

Highlights

The immune system requires checkpoints to prevent reactions against self-antigens
B cells were isolated from spleens of naive DBA/1J mice and activated T cell independently with anti-B cell receptor (BCR) IgM and the Toll-like receptor (TLR)9 agonist CpG
We determined whether regulatory B cell (Breg) generated by TLR9 activation show enhanced expression of these proteins. We demonstrated that both programmed death ligand 1 (PD-L1) and Fas ligand (FasL) were significantly up-regulated on TLR9-activated B cells in comparison to untreated cells (Fig 7E)

Summary

Introduction

The immune system requires checkpoints to prevent reactions against self-antigens. Faulty checkpoint inhibition can lead to multiple disorders and autoimmune diseases. While central tolerance is responsible for deleting autoreactive adaptive immune cells, peripheral tolerance is considered as a second-line checkpoint that controls lymphocytes that escaped deletion in primary lymphoid tissues. The sympathetic nervous system (SNS) might be one regulator of these processes since several studies showed that SNS influences the development and severity of autoimmune diseases, like rheumatoid arthritis (RA) [1].

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Results

Conclusion