CD11b suppresses TLR activation of nonclassical monocytes to reduce primary graft dysfunction after lung transplantation
Melissa Querrey, … , Ankit Bharat, G.R. Scott Budinger
Melissa Querrey, … , Ankit Bharat, G.R. Scott Budinger
Published July 15, 2022
Citation Information: J Clin Invest. 2022;132(14):e157262. https://doi.org/10.1172/JCI157262.
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Research Article Immunology

CD11b suppresses TLR activation of nonclassical monocytes to reduce primary graft dysfunction after lung transplantation

Abstract

Primary graft dysfunction (PGD) is the leading cause of postoperative mortality in lung transplant recipients and the most important risk factor for development of chronic lung allograft dysfunction. The mechanistic basis for the variability in the incidence and severity of PGD between lung transplant recipients is not known. Using a murine orthotopic vascularized lung transplant model, we found that redundant activation of Toll-like receptors 2 and 4 (TLR2 and -4) on nonclassical monocytes activates MyD88, inducing the release of the neutrophil attractant chemokine CXCL2. Deletion of Itgam (encodes CD11b) in nonclassical monocytes enhanced their production of CXCL2 and worsened PGD, while a CD11b agonist, leukadherin-1, administered only to the donor lung prior to lung transplantation, abrogated CXCL2 production and PGD. The damage-associated molecular pattern molecule HMGB1 was increased in peripheral blood samples from patients undergoing lung transplantation after reperfusion and induced CXCL2 production in nonclassical monocytes via TLR4/MyD88. An inhibitor of HMGB1 administered to the donor and recipient prior to lung transplantation attenuated PGD. Our findings suggest that CD11b acts as a molecular brake to prevent neutrophil recruitment by nonclassical monocytes following lung transplantation, revealing an attractive therapeutic target in the donor lung to prevent PGD in lung transplant recipients.

Authors

Melissa Querrey, Stephen Chiu, Emilia Lecuona, Qiang Wu, Haiying Sun, Megan Anderson, Megan Kelly, Sowmya Ravi, Alexander V. Misharin, Daniel Kreisel, Ankit Bharat, G.R. Scott Budinger

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Figure 8

LA-1 prevents PGD in mice.

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LA-1 prevents PGD in mice. (A) Schematic for the allogeneic transplantat...
(A) Schematic for the allogeneic transplantations. Donor mice were C57BL/6J and recipients were BALB/c. LA-1 was administered (2 mg/kg intravenously) only to the donor. (B) Lung allografts were harvested 24 hours after lung transplantation and neutrophil numbers were quantified from lung homogenates using flow cytometry. *P = 0.0128 by 1-way ANOVA with Dunnett’s correction for multiple comparisons, as detailed in Supplemental Figure 5. (C) Representative H&E staining of allografts with and without glycyrrhizin treatment. (D) Acute lung injury (ALI) scores for the images in C. *P = 0.0122 by 1-way ANOVA with Dunnett’s correction for multiple comparisons, as detailed in Supplemental Figure 5. (E) Lung sections from allografts of mice with and without glycyrrhizin treatment using RNAscope and immunohistochemical staining (blue: nuclear stain, green: MyD88, magenta: Nr4a1). Original magnification, ×400. (F) MyD88 particle counts per Nr4a1-positive NCM in allografts with and without LA-1 treatment. **P = 0.0070 by 1-way ANOVA with Dunnett’s multiple comparisons test, as detailed in Supplemental Figure 5. Each symbol represents an individual mouse. The controls for ALI score and average particle number per cell are identical to those in Figures 4 and 6.