Khatri et al. report that JAK-STAT activation in airways following human lung transplantation contributes to upregulation of MHC-I in donor basal cells and alloimmune cytotoxic T cell–mediated basal cell death. The cover image shows a bronchiole with epithelial cell loss accompanied by peribronchiolar fibrosis, a defining histologic feature in bronchiolitis obliterans, a form of chronic lung allograft dysfunction after lung transplant.
Although the expression of Mex3 RNA binding family member B (MEX3B) is upregulated in human nasal epithelial cells (HENCs) predominately in the eosinophilic chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) subtype, its functions as an RNA binding protein in airway epithelial cells remain unknown. Here, we revealed the role of MEX3B based on different subtypes of CRS, and demonstrated that MEX3B decreased TGF-β receptor III (TGFBR3) mRNA level by binding to its 3’ UTR and reducing its stability in HNECs. TGF-βR3 was found to be a TGF-β2 specific coreceptor in HNECs. Knocking down or overexpressing MEX3B promoted or inhibited TGF-β2-induced phosphorylation of Smad2 in HNECs, respectively. TGF-βR3 and p-Smad2 levels were downregulated in CRSwNP compared with controls and CRS without nasal polyps (CRSsNP), with a more prominent downregulation in the eosinophilic CRSwNP. TGF-β2 promoted collagen production in HNECs. Collagen abundance decreased and edema scores increased in CRSwNP compared to control, again more prominently in the eosinophilic type. Collagen expression in eosinophilic CRSwNP was negatively correlated with MEX3B but positively correlated with TGF-βR3. These results suggest that MEX3B inhibits tissue fibrosis in eosinophilic CRSwNP by downregulating epithelial cell TGFBR3 expression; consequently, MEX3B might be a valuable therapeutic target against eosinophilic CRSwNP.
Jin-Xin Liu, Chen Ao-Nan, Qihong Yu, Ke-Tai Shi, Yi-Bo Liu, Cui-Lian Guo, Zhe-Zheng Wang, Yin Yao, Li Pan, Xiang Lu, Kai Xu, Heng Wang, Ming Zeng, Chaohong Liu, Robert P. Schleimer, Ning Wu, Bo Liao, Zheng Liu
Vascular smooth muscle-derived Sca1+ adventitial progenitor (AdvSca1-SM) cells are tissue resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and extracellular matrix. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the AdvSca1-SM-to-myofibroblast transition are unclear. We show that the chromatin remodeler, Smarca4/Brg1, facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein was upregulated in AdvSca1-SM cells after acute vascular injury and pharmacological inhibition of Brg1 by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; PFI blocked TGF-β1-induced phenotypic transition. Similarly, genetic knockdown of Brg1 in vivo reduced adventitial remodeling and fibrosis and reversed AdvSca1-SM-to-myofibroblast transition in vitro. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal intergenic sites of stemness genes and recruitment to promoter regions of myofibroblast-related genes, which was blocked by PFI-3. These data shed insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating the AdvSca1-SM phenotype will provide important anti-fibrotic clinical benefit.
Austin J. Jolly, Sizhao Lu, Allison M. Dubner, Keith A. Strand, Marie F. Mutryn, Aaron Pilotti-Riley, Etienne P. Danis, Raphael A. Nemenoff, Karen S. Moulton, Mark W. Majesky, Mary C.M. Weiser-Evans
Invariant Natural Killer T (iNKT) cells act at the interface between lipid metabolism and immunity, due to their restriction to lipid antigens presented on CD1d by antigen presenting cells (APC). How foreign lipid antigens are delivered to APC remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), Isoglobotrihexosylceramide (iGb3) and OCH, a sphingosine-truncated analogue of αGalCer, with very-low-density (VLDL) and/or low-density (LDL) lipoproteins in vitro and in vivo. We demonstrate LDL receptor (LDLR)-mediated uptake of lipoprotein-αGalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a novel mechanism of lipid antigen delivery to APCs, and provides further insight in the immunological capacities of circulating lipoproteins.
Suzanne E. Engelen, Francesca A. Ververs, Angela Markovska, B. Christoffer Lagerholm, Jordan M. Kraaijenhof, Laura I.E. Yousif, Yasemin-Xiomara Zurke, Can M.C. Gulersonmez, Sander Kooijman, Michael Goddard, Robert J. van Eijkeren, Peter J. Jervis, Gurdyal S. Besra, Saskia Haitjema, Folkert W. Asselbergs, Eric Kalkhoven, Hidde L. Ploegh, Marianne Boes, Vincenzo Cerundolo, G. Kees Hovingh, Mariolina Salio, Edwin C.A. Stigter, Patrick C.N. Rensen, Claudia Monaco, Henk S. Schipper
Loss of function mutations in the DNA methyltransferase 3A (DNMT3A) are seen in a large number of AML patients with normal cytogenetics and are frequently associated with poor prognosis. DNMT3A mutations are an early pre-leukemic event, which when combined with other genetic lesions result in full blown leukemia. Here, we show that loss of Dnmt3a in HSC/Ps results in myeloproliferation, which is associated with hyperactivation of the PI3Kinase pathway. PI3Kα/β or the PI3Kα/δ inhibitor treatment partially corrects myeloproliferation, although the partial rescue is more efficient in response to the PI3Kα/β inhibitor treatment. In vivo RNA-seq analysis on drug treated Dnmt3a–/– HSC/Ps showed a reduction in the expression of genes associated with chemokines, inflammation, cell attachment and extracellular matrix compared to controls. Remarkably, drug treated leukemic mice showed a reversal in the enhanced fetal liver HSC like gene signature observed in vehicle treated Dnmt3a–/– LSK cells as well as a reduction in the expression of genes involved in regulating actin cytoskeleton-based functions including the RHO/RAC GTPases. In a human PDX model bearing DNMT3A mutant AML, PI3Kα/β inhibitor treatment prolonged their survival and rescued the leukemic burden. Our results identify a new target for treating DNMT3A mutation driven myeloid malignancies.
Lakshmi Reddy Palam, Baskar Ramdas, Katelyn M. Pickerell, Santhosh Kumar Pasupuleti, Rahul Kanumuri, Annamaria Cesarano, Megan Szymanski, Bryce M. Selman, Utpal P. Davé, George Sandusky, Fabiana Perna, Sophie Paczesny, Reuben Kapur
Several pre-clinical studies have demonstrated that certain cytotoxic drugs enhance metastasis, but the importance of host responses triggered by chemotherapy in regulating cancer metastasis has not been fully explored. Here, we showed that multi-dose Gemcitabine (GEM) treatment promoted breast cancer lung metastasis in a transgenic spontaneous breast cancer model. GEM treatment significantly increased accumulation of CCR2+ macrophages and monocytes in the lungs of tumor-bearing as well as tumor-free mice. These changes were largely caused by chemotherapy induced reactive myelopoiesis that is biased toward monocyte development. Mechanistically, enhanced production of mitochondrial ROS was observed in GEM treated BM LSK cells and monocytes. Treatment with the mitochondrial targeted antioxidant abrogated GEM induced hyper-differentiation of BM progenitors. In addition, GEM treatment induced up-regulation of host cell derived CCL2, and knockout CCR2 signaling abrogated the pro-metastatic host response induced by chemotherapy. Furthermore, chemotherapy treatment resulted in the upregulation of coagulation factor X (FX) in lung interstitial macrophages. Targeting activated FX (FXa) using FXa inhibitor or F10 gene knockdown reduced pro-metastatic effect of chemotherapy. Together, these studies suggest a novel mechanism for chemotherapy induced metastasis via the host response induced accumulation of monocytes/macrophages and interplay between coagulation and inflammation in the lungs.
Caijun Wu, Qian Zhong, Rejeena Shrestha, Jingzhi Wang, Xiaoling Hu, Hong Li, Eric C. Rouchka, Jun Yan, Chuanlin Ding
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