B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling
Khashayar Farahnak, … , Daniel Kreisel, Ruben G. Nava
Khashayar Farahnak, … , Daniel Kreisel, Ruben G. Nava
Published January 23, 2024
Citation Information: J Clin Invest. 2024;134(6):e170118. https://doi.org/10.1172/JCI170118.
View: Text | PDF
Research Article Immunology

B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling

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.

Authors

Khashayar Farahnak, Yun Zhu Bai, Yuhei Yokoyama, Deniz B. Morkan, Zhiyi Liu, Junedh M. Amrute, Alejandro De Filippis Falcon, Yuriko Terada, Fuyi Liao, Wenjun Li, Hailey M. Shepherd, Ramsey R. Hachem, Varun Puri, Kory J. Lavine, Andrew E. Gelman, Ankit Bharat, Daniel Kreisel, Ruben G. Nava

×

Figure 3

Lung function improvement in the absence of B cells is associated with a significant reduction in the abundance of CCR2+ classical monocytes in the lung.

Options: View larger image (or click on image) Download as PowerPoint
Lung function improvement in the absence of B cells is associated with a...
(A) Flow cytometry gating strategy for classical monocytes (CD45+CD11b+Ly6G–Ly6ChiCCR2+) between hilar clamped B6 WT mice and μMT mice. (B) Percentage of and (C) total number per milligram of lung tissue of classical monocytes recruited to the lung after IRI in B6 WT mice and μMT mice with and without adoptive transfer of B6 WT B cells. (D) Positive correlation between number of B cells and number of classical monocytes in the lung after IRI. Pearson’s correlation coefficient (r) was significant. (E) Quantification and representative flow cytometry dot plots of extravascular classical monocytes in the lungs after adoptive transfer of B6 WT B cells, which are significantly lower in μMT mice compared with B6 WT and μMT mice with WT B cells. Lung recipients were treated with anti-CD20–specific or isotype control antibodies and analyzed for (F) intragraft B cell depletion, (G) lung function (PaO2), (H) the relative proportion and total number of classical monocytes, and (I) neutrophil extravasation. n = 4–8. Data shown in E and F are representative dot and contour plots where n > 4 per group. Results are presented as mean ± SEM. (B, C, and E) P values were calculated by Kruskal-Wallis test. *P < 0.05, **P < 0.01. (G–I) P values were calculated by Mann-Whitney test. *P < 0.05.