1. B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling
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Farahnak, Khashayar, Bai, Yun Zhu, Yokoyama, Yuhei, Morkan, Deniz B., Liu, Zhiyi, Amrute, Junedh M., De Filippis Falcon, Alejandro, Terada, Yuriko, Liao, Fuyi, Li, Wenjun, Shepherd, Hailey M., Hachem, Ramsey R., Puri, Varun, Lavine, Kory J., Gelman, Andrew E., Bharat, Ankit, Kreisel, Daniel, and Nava, Ruben G.
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Thermo Fisher Scientific Inc. ,Transplantation of organs, tissues, etc. ,Medical research ,Medicine, Experimental ,Scientific equipment and supplies industry ,Lung diseases ,Immune response ,B cells ,Health care industry ,Washington University. School of Medicine - Abstract
Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated 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 observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes 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., Introduction Primary graft dysfunction (PGD) is a common early complication after lung transplantation that adversely affects both shortand long-term outcomes. This includes both early morbidity and mortality as well as [...]
- Published
- 2024
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