Jun Cai, MD, PhD, awarded ATS 2020 Science and Innovation Center Abstract Award

Jun Cai, MD, PhD, was awarded the 2020 Science and Innovation Center Abstract Award by the American Thoracic Society for his abstract entitled: “Myeloid-Derived Suppressor Cells Ameliorate Lung Ischemia-Reperfusion Injury Via Regulation of IL-17 and IL-10.”

This award was bestowed during the Assembly for Allergy, Immunology and Inflammation (AII) by the Science and Innovation Center Award Selection Committee.

Notably, Cai’s abstract explored how the immune mechanisms of donor graft dysfunction involve myeloid-derived suppressor cells that can offer protective immunosuppression in patients with post-lung transplant injury.

For the full abstract, read below.

Myeloid-derived suppressor cells ameliorate lung ischemia-reperfusion injury via regulation of IL-17 and IL-10

Jun Cai1, Gang Su1, Xiaoyan Qi1, Amir Emtiazjoo2, Philip Efron1, Mark Brantly2, Borna Mehrad2, Tiago Machuca1, Lyle Moldawer1, Gilbert R. Upchurch, Jr.1, Ashish K. Sharma1,2

1Department of Surgery, University of Florida, Gainesville, FL

2Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL

Rationale: The success of lung transplantation is limited by primary graft dysfunction due to ischemia-reperfusion (IR) injury. Our hypothesis is that innate myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of myeloid precursor and progenitor cells, can exhibit immunosuppressive capability to prevent lung IR injury and allograft rejection.

Methods: C57BL/6 wild-type (WT) mice underwent sham surgery or lung IR (1hr left lung ischemia followed by 6hrs reperfusion) using an in vivo hilar-ligation model. Adoptive transfer of CD11b+Gr-1+ MDSCs (3×106 cells given in 100ml saline intratracheally) was performed 1hr prior to IR. Lung function was measured using an isolated, buffer-perfused apparatus. Flow cytometry analysis was performed on lung tissue to quantify MDSCs. Cytokine and myeloperoxidase levels were measured in bronchoalveolar lavage fluid, and lung injury was assessed by neutrophil infiltration (immunohistochemistry). Co-cultures of MDSCs with primary CD4+ iNKT cells or CD4+CD25+FoxP3+ T regulatory cells (Tregs) were exposed to hypoxia/reoxygenation (HR; 3hrs/3hr) to quantify cytokine expression in supernatants. Groups were compared using ANOVA followed by post hoc Tukey’s test and data is presented as mean±S.E.

Results: Lung dysfunction (increased airway resistance and pulmonary artery pressure as well as decreased pulmonary compliance) occurred in mice after lung IR compared to sham. Adoptive transfer of CD11b+Gr-1+ MDSCs showed significant protection from lung dysfunction compared to vehicle (saline) mice after IR, as shown by decreased airway resistance (0.9±0.05 vs. 1.8±0.04 cm H2O/ml/sec; p<0.0001) and pulmonary artery pressure (7.6±0.3 vs. 12.2±0.2 cm H2O; p<0.0001) as well as increased pulmonary compliance (4.9±0.1 vs. 2.4±0.1 ml/cm H2O; p<0.0001; n=7/group). Flow cytometry analysis demonstrated a significant increase in CD11b+Gr-1+ MDSCs in murine lungs after IR compared to sham (31.8±3.2 vs. 18.6±3.2%; n=8/group; p=0.01). Lung inflammation and injury were also significantly attenuated in mice treated with MDSCs compared to saline-treated mice as seen by mitigation of proinflammatory cytokines (IL-17, TNF-a, CXCL1, MCP-1, RANTES) as well as increase in anti-inflammatory IL-10 expression, decreased myeloperoxidase levels (33.9±4.3 vs. 104.2±5.2 ng/ml; p<0.01) and attenuation of neutrophil infiltration. Co-culture of MDSCs with iNKT cells significantly mitigated HR-induced pro-inflammatory IL-17A secretion, whereas co-culture of MDSCs with Tregs upregulated anti-inflammatory IL-10 production after HR.

Conclusions: Our results suggest that MDSCs can interact with immune cells to induce tolerance for protection against lung IR injury. The crosstalk between MDSCs with iNKT cells and Tregs can mitigate inflammation via IL-17 and IL-10 to ameliorate lung IR injury.