Basophilic exosomes promote SLE development via exacerbating B cell activation through the lncRNA ENST00000537616/miR-330-5p/KRAS axis.

INTRODUCTION

Uncontrolled B-cell activation in systemic lupus erythematosus (SLE) induces autoantibody production and inflammation and causes tissue damage. Basophils have been shown to promote B cell activation in SLE; however, the molecular mechanisms involved remain nebulous.

OBJECTIVE

To elucidate the role of basophilic exosomes in B-cell activation and explore the associated molecular mechanisms in SLE.

METHODS

We employed a multifaceted approach combining human cell studies and animal models and assessed the effects of human basophil-derived exosomes on B cell activation in SLE patients by evaluating activation markers following exosome uptake. Furthermore, we used a basophil-depleted lupus mouse model to examine the impact of basophilic exosomes on disease progression and conducted transcriptomic analysis of basophilic exosomes to identify key molecular regulators. Finally, we explored the therapeutic potential of targeting lncRNA ENST00000537616 by intervening in its expression in humanized SLE mouse models.

RESULTS

Human-activated basophil-derived exosomes significantly enhanced the activation of B cells from SLE patients in vitro. In the basophil-depleted lupus mouse model, activated basophilic exosomes induced excessive splenic immune cell proliferation and exacerbated renal dysfunction. Transcriptomic analysis revealed lncRNA ENST00000537616 as a key regulator released by activated basophilic exosomes, promoting B cell activation. LncRNA ENST00000537616 inhibition in a humanized SLE mouse model significantly attenuated immune hyperactivation and improved renal function, mirroring the effects of activated basophilic exosome inhibition. Mechanistically, activated basophilic exosomes facilitated B cell activation via the lncRNA ENST00000537616/miR-330-5p/KRAS axis.

CONCLUSIONS

This study provides novel insights into the pathogenesis of SLE by elucidating the role of basophilic exosomes and the lncRNA ENST00000537616/miR-330-5p/KRAS axis in B cell activation.