Autophagy differentially regulates tissue tolerance of distinct target organs in graft-versus-host disease models
Katherine Oravecz-Wilson, Emma Lauder, Austin Taylor, Laure Maneix, Jeanine L. Van Nostrand, Yaping Sun, Lu Li, Dongchang Zhao, Chen Liu, Pavan Reddy
Katherine Oravecz-Wilson, Emma Lauder, Austin Taylor, Laure Maneix, Jeanine L. Van Nostrand, Yaping Sun, Lu Li, Dongchang Zhao, Chen Liu, Pavan Reddy
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Research Article Immunology

Autophagy differentially regulates tissue tolerance of distinct target organs in graft-versus-host disease models

Abstract

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.

Authors

Katherine Oravecz-Wilson, Emma Lauder, Austin Taylor, Laure Maneix, Jeanine L. Van Nostrand, Yaping Sun, Lu Li, Dongchang Zhao, Chen Liu, Pavan Reddy

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Figure 2

Albumin-Cre+ Atg5–/– mice display greater mortality after allo-BMT in the absence of autophagy in the liver.

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Albumin-Cre+ Atg5–/– mice display greater mortality after allo-BMT in th...
Alb-Cre+ Atg5–/– mice (B6 Albumin-KO) and Alb-Cre– Atg5fl/fl littermate controls (B6 WT) on a C57BL/6 background were used as recipients in syn- and MHC-mismatched allo-BMT. Mice were monitored weekly for survival (A), weight change (B), and GVHD score (C). (D) Liver weights. (E) Liver scored for GVHD pathology at day 7 after BMT with representative micrographs (original magnification, ×20) with H&E-stained tissue sections. (F) Liver function test levels at day 7 after BMT of bilirubin, alkaline phosphatase, and alanine aminotransferase (ALT) in B6 Albumin-KO versus B6 WT mice. (G) Phenotype of donor (H2Kd+) CD3+ T cells at day 4 after BMT, from liver, by flow cytometry. (H) Percentage of IFN-γ– and TNF-α–producing donor (H2Kd+) CD4+ T cells in livers from B6 Albumin-KO and B6 WT mice at day 4 after BMT, measured by flow cytometry. In A–C, BMT data represent a combination of 2 independent experiments (Syn WT, n = 4; Syn Albumin-KO, n = 4; Allo B6 WT, n = 10; Allo B6 Albumin-KO, n = 10). D represents data comparing 2 groups (Allo B6 WT, n = 9; Allo Albumin-KO, n = 9). E represents combined data from 2 independent experiments analyzed at day 7 after BMT (Allo B6 WT, n = 6; Allo Albumin-KO, n = 8). F represents liver panel analysis on day 7 after allo-BMT (Allo B6 WT, n = 3; Allo B6 Albumin-KO, n = 3). G and H represent analysis on day 4 after allo-BMT (B6 WT, n = 3; B6 Albumin-KO, n = 4). Significance was determined using log-rank (Mantel-Cox) test for survival data. Significance was determined using unpaired t test for weight and GVHD score. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.