B cells mediate lung ischemia-reperfusion injury by recruitment of CCR2+-classical monocytes via synergistic BCR-TLR4 signaling

ABSTRACT: Ischemia reperfusion injury (IRI)-mediated primary graft dysfunction (PGD) adversely impacts both short- and long-term outcomes after lung transplantation, a procedure which remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells can regulate adaptive immune responses through antibody production, antigen presentation and secretion of cytokines, their role in lung IRI is not well understood. Here, we demonstrate by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observe that lung-infiltrating B cells produce the monocyte chemokine CCL7 in Toll-like receptor 4 (TLR4)-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We find that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborate our findings in reperfused human lungs, where we observe a correlation between B cell infiltration and CM recruitment after transplantation. This study uncovers a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE249242 | GEO | 2024/03/20

REPOSITORIES: GEO