Session Time: 6:00pm-7:00pm
Presentation Time: 6:20pm-6:25pm
*Purpose: Bronchiolitis obliterans (BOS) remains a major cause of death for lung transplant recipients, and the mechanisms that drive BOS remain poorly understood. It is known that genetically encoded deficiencies in mitophagy, a specialized form of autophagy which targets the removal of damaged mitochondria, promote disease but it is unclear if they play a role in BOS. Prior work has shown that the rs2241880 mutation in ATG16L1, an autophagy related protein, leads to protein instability resulting in deficiency of ATG16L1 in monocyte-derived (Mo-cells) macrophages. We previously observed that human lung recipient carriers of rs2241880 had accelerated BOS. Therefore, we analyzed the effects of ATG16L1 deficiency in Mo-CD11c+ cells in a mouse orthotopic lung transplant model of BOS.
*Methods: CD11cCreATG16L1flox/flox (ATG16L1Δ/Δ) and control CD11cCre recipients received major MHC-mismatched FVB lungs, with immunosuppression to induce acceptance. Following induced epithelial injury, allografts were assessed for obliterative airway lesions for up to 28 days. Intragraft Mo-CD11c+ cells were analyzed for bulk RNA sequencing and by FACS for mitochondrial mass and ROS production. Mitophagic flux was visualized by confocal microscopy using Mt-kiema mitophagy reporter mice. Metabolic activity was characterized using a Seahorse XF analyzer. Alloimmunity was examined via T cell proliferation assays and ELISA.
*Results: ATG16L1Δ/Δ recipients showed severe and accelerated OB compared to controls. RNAseq analysis of ATG16L1Δ/Δ deficient intra-graft Mo-derived cells demonstrated a loss of transcripts that encode subunits of mitochondria electron complex I, II and V. Confocal and FACS revealed higher MHCII+, attenuated mitophagic flux, high mitochondrial mass and elevated ROS production in ATG16L1Δ/Δ. In line with these observations were decreased maximal mitochondrial respiratory capacity, lower mitochondrial ATP production and increased utilization of glycolysis; as well as increased T cell proliferation and higher IL1-β suggesting metabolic adaptation of an M1 inflammatory phenotype.
*Conclusions: These data reveal a new role for ATG16L1 as a regulator of mitochondrial quality control and alloimmunity with implications for lung recipients that carry the ATG16L1 rs2241880 mutation.
To cite this abstract in AMA style:Cano M, Zhou D, Kreisel D, Chen C, Pugh K, Byers D, Hachem R, Gelman A. Accelerated Bronchiolitis Obliterans After Lung Transplant Promoted by an ATG16L1 Mutation is Coupled to Mitochondrial Damage and Metabolic Alterations in Monocyte-derived Antigen Presenting Cells [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/accelerated-bronchiolitis-obliterans-after-lung-transplant-promoted-by-an-atg16l1-mutation-is-coupled-to-mitochondrial-damage-and-metabolic-alterations-in-monocyte-derived-antigen-presenting-cells/. Accessed June 13, 2021.
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