AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival
Collin Z. Jordan, Matthew Tunbridge, Irma Husain, Hiroki Kitai, Miriam E. Dilts, Olivia K. Fay, Koki Abe, Catherine Xiang, Jean Kwun, Tomokazu Souma, Edward B. Thorp, Xunrong Luo
Collin Z. Jordan, Matthew Tunbridge, Irma Husain, Hiroki Kitai, Miriam E. Dilts, Olivia K. Fay, Koki Abe, Catherine Xiang, Jean Kwun, Tomokazu Souma, Edward B. Thorp, Xunrong Luo
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Research Article Immunology Transplantation

AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival

Abstract

Innate immune cells are important in the initiation and potentiation of alloimmunity in transplantation. Immediately upon organ anastomosis and reperfusion, recipient monocytes enter the graft from circulation and differentiate to inflammatory macrophages to promote allograft inflammation. However, factors that drive their differentiation to inflammatory macrophages are not understood. Here, we show that the receptor tyrosine kinase AXL was a key driver of early intragraft differentiation of recipient infiltrating monocytes to inflammatory macrophages in the presence of allogeneic stimulation and cell-to-cell contact. In this context, the differentiated inflammatory macrophages were capable of efficient alloantigen presentation and allostimulation of T cells of the indirect pathway. Consequently, early and transient AXL inhibition with the pharmacological inhibitor bemcentinib resulted in a profound reduction of initial allograft inflammation and a significant prolongation of allograft survival in a murine heart transplant model. Our results support further investigation of AXL inhibition as part of an induction regimen for transplantation.

Authors

Collin Z. Jordan, Matthew Tunbridge, Irma Husain, Hiroki Kitai, Miriam E. Dilts, Olivia K. Fay, Koki Abe, Catherine Xiang, Jean Kwun, Tomokazu Souma, Edward B. Thorp, Xunrong Luo

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Figure 6

Transient AXL inhibition prolongs murine heart allograft survival.

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Transient AXL inhibition prolongs murine heart allograft survival. (A) C...
(A) Cardiac allograft survival in untreated (CT), transient bemcentinib-treated (BEM) recipients, and AXL-KO mice, plotted as a function of days after transplant with log-rank survival analysis and correction for multiple comparison. *P < 0.05, ***P < 0.001 (n = 3–7 per group). (B) Representative immunofluorescence imaging of F4/80+ Mϕs (red), cardiomyocytes (green, autofluorescence), and nuclei (blue, DAPI) in a heart allograft at time of rejection (day 8) in CT recipients and simultaneous time point of stable graft function in BEM recipients. Scale bar: 100 μm (at ×20), 40 μm (at ×60). Quantification graph of F4/80+ Mϕ staining area in heart allograft sections (n = 4–5 mice per group; data shown as mean of 4 representative images taken across allograft per recipient). Analysis by t test. *P < 0.05. (C) Experimental design schematic of a mouse heterotopic heart transplantation model, in which B6 mice were transplanted with a BALB/c heart allograft. CT recipients were left untreated for the duration of the experiment, recipients in the αCD154 group were given 2 doses of perioperative αCD154 (D0 + D2) monotherapy, and recipients in the BEM + αCD154 group were provided transient bemcentinib (D-1 to D+10) and perioperative αCD154 (D0 + D2) dual therapy. (D) Heart allograft survival in CT, αCD154 monotherapy, and BEM + αCD154 dual therapy–treated recipients, plotted as a function of days after transplant (n = 5–7 per group), with log-rank survival analysis and correction for multiple comparison. **P < 0.01. CT group (n = 7) from A was used for comparison.