MMP-12 blockade in B lymphocytes inhibits the formation of inducible BALTs and alleviates neutrophilic allergic airway inflammation

Inducible Bronchus-Associated Lymphoid Tissue (iBALTs), the tertiary immune organs in the lungs, have been implicated in various pulmonary diseases. The formation and roles of iBALTs related to severe asthma, however, remain unclear. iBALTs was located near the area of bronchi and vessels in the severe asthma murine model induced by house dust mite (HDM) extract and lipopolysaccharides (LPS). Repeated sensitizations promoted the formation of iBALTs, which disappeared 2 weeks post last HDM challenge. The neutralizing antibody of CXCL13 prevented the formation of iBALTs but failed to relieve the airway inflammation. B lymphocytes dominated in iBALTs. Compared with the control group, severe asthma group had increased IgE secreting cells. Bulk RNA-seq reveled the elevated MMP-12 in pulmonary B cells. MMP408, a specific MMP-12 inhibitor, reduced iBALTs formation. Moreover, AAV-6 targeting down MMP-12 in B lymphocytes blocked iBALTs and ameliorated the inflammation. These results indicated that MMP-12 from B lymphocytes motivated the aggregation of B lymphocytes, promoted the formation of iBALTs and further sharpened the inflammation of severe asthma.