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BACKGROUND. Rejection is the primary barrier to broader implementation of vascularized composite allografts (VCA), including face and limb transplants. The immunologic pathways activated in face transplant rejection have not been fully characterized. METHODS. Utilizing skin biopsies prospectively collected over nine years from seven face transplant patients, we studied rejection by gene expression profiling, histology, immunostaining and T cell receptor sequencing. RESULTS. Grade 1 rejection did not differ significantly from non-rejection, suggesting that it does not represent a pathologic state and that watchful waiting is warranted. In Grade 2, there was a balanced upregulation of both pro-inflammatory T cell activation pathways and anti-inflammatory checkpoint and immunomodulatory pathways, with a net result of no tissue injury. In Grade 3, IFNγ-driven inflammation, antigen presenting cell activation and infiltration of the skin by proliferative T cells bearing markers of antigen specific activation and cytotoxic effector molecules tipped the balance towards tissue injury. Rejection of VCA and solid organ transplants had both distinct and common features. VCA rejection was uniquely associated with upregulation of immunoregulatory genes, including SOCS1, induction of lipid antigen-presenting CD1 proteins, and infiltration by T cells predicted to recognize CD1b and CD1c. CONCLUSIONS. Our findings suggest that the distinct features of VCA rejection reflect the unique immunobiology of skin and that enhancing cutaneous immunoregulatory networks may be a useful strategy in combatting rejection.
Thet Su Win, William J. Crisler, Beatrice Dyring-Andersen, Rachel Lopdrup, Jessica E. Teague, Qian Zhan, Victor Barrera, Shannan J. Ho Sui, Sotirios Tasigiorgos, Naoka Murakami, Anil Chandraker, Stefan G. Tullius, Bohdan Pomahac, Leonardo V. Riella, Rachael Clark
SUMOylation emerged as the inducer for the sorting of bioactive molecules into extracellular vesicles (EVs) triggering lymphangiogenesis, further driving tumor lymph node (LN) metastasis, but the precise mechanisms remain largely unclear. Herein, we identified that bladder cancer (BCa) cell-secreted EVs mediated the intercellular communication with human lymphatic endothelial cells (HLECs) through the transmission of a long noncoding RNA ELNAT1, and promoted lymphangiogenesis and LN metastasis in a SUMOylation-dependent manner in both cultured BCa cell lines and mouse models. Mechanistically, ELNAT1 induced UBC9 overexpression to catalyze the SUMOylation of hnRNPA1 at lysine-113 residue, which mediated the recognition of ELNAT1 by endosomal sorting complex required for transport (ESCRT) and facilitated their packaging into EVs. EV-mediated ELNAT1 was specifically transmitted into HLECs and epigenetically activated SOX18 transcription to induce lymphangiogenesis. Importantly, blocking the SUMOylation of tumor by downregulating UBC9 expression markedly reduced lymphatic metastasis in EV-mediated ELNAT1-treated BCa in vivo. Clinically, EV-mediated ELNAT1 was correlated with LN metastasis and poor prognosis of patients with BCa. These findings highlight a molecular mechanism that EV-mediated ELNAT1/UBC9/SOX18 regulatory axis promotes the lymphangiogenesis and LN metastasis of BCa in a SUMOylation-dependent manner, and implicate ELNAT1 as an attractive therapeutic target for LN metastatic BCa.
Changhao Chen, Hanhao Zheng, Yuming Luo, Yao Kong, Mingjie An, Yuting Li, Wang He, Bowen Gao, Yue Zhao, Hao Huang, Jian Huang, Tianxin Lin
Autophagy modulates lipid turnover, cell survival, inflammation and atherogenesis. Scavenger receptor class B type I (SR-BI) plays a crucial role in lysosome function. Here, we demonstrate that SR-BI regulates autophagy in atherosclerosis. SR-BI deletion attenuated lipid-induced expression of autophagy mediators in macrophages and atherosclerotic aortas. Consequently, SR-BI deletion resulted in 1.8- and 2.5-fold increases in foam cell formation and apoptosis, respectively, and increased oxidized LDL-induced inflammatory cytokine expression. Pharmacological activation of autophagy failed to reduce lipid content or apoptosis in Sr-b1-/- macrophages. SR-BI deletion reduced both basal and inducible levels of transcription factor EB (TFEB), a master regulator of autophagy, causing decreased expression of autophagy genes encoding VPS34 and Beclin-1. Notably, SR-BI regulated Tfeb expression by enhancing PPARα activation. Moreover, intracellular macrophage SR-BI localized to autophagosomes, where it formed cholesterol domains resulting in enhanced association of Barkor and recruitment of the VPS34/Beclin-1 complex. Thus, SR-BI deficiency led to lower VPS34 activity in macrophages and in atherosclerotic aortic tissues. Overexpression of Tfeb or Vps34 rescues the defective autophagy in Sr-b1-/- macrophages. Taken together, macrophage SR-BI regulates autophagy via Tfeb expression and recruitment of the VPS34/Beclin-1 complex, thus identifying previously unrecognized roles for SR-BI and novel targets for the treatment of atherosclerosis.
Huan Tao, Patricia G. Yancey, John L. Blakemore, Youmin Zhang, Lei Ding, W. Gray Jerome, Jonathan D. Brown, Kasey C. Vickers, MacRae F. Linton
The excitability of interneurons requires Nav1.1, the α subunit of voltage-gated sodium channel. Nav1.1 deficiency and mutations reduce interneuron excitability, a major pathological mechanism for epilepsy syndromes. However, the regulatory mechanisms of Nav1.1 expression remain unclear. Here we provide evidence that neddylation is critical to Nav1.1 stability. Mutant mice lacking Nae1, an obligatory component of the E1 ligase for neddylation, in parvalbumin-positive interneurons (PVINs) exhibited spontaneous epileptic seizures and premature death. Electrophysiological studies indicate that Nae1 deletion reduced in PVIN excitability and GABA release, and consequently increased the network excitability of pyramidal neurons (PyNs). Further analysis revealed a reduction in sodium current density, not a change in channel property, in mutant PVINs and decreased Nav1.1 protein level. These results suggest that insufficient neddylation in PVINs reduces Nav1.1 stability and thus the excitability of PVINs; ensuing increased PyN activity causes seizures in mice. In agreement, Nav1.1 was found reduced by proteomic analysis that revealed abnormality in synapses and metabolic pathways. Our findings, for the first time, described a role of neddylation in maintaining Nav1.1 stability for PVIN excitability and reveal a new mechanism in pathogenesis of epilepsy.
Wenbing Chen, Bin Luo, Nannan Gao, Haiwen Li, Hongsheng Wang, Lei Li, Wanpeng Cui, Lei Zhang, Dong Sun, Fang Liu, Zhaoqi Dong, Xiao Ren, Hongsheng Zhang, Huabo Su, Wen-Cheng Xiong, Lin Mei
A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multi-omic analyses using 2,872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance (155 unique variants with allele frequency < 1%; 12.9% carrier rate). We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C (FDR=2.6e-5), which is induced also in mucosal biopsies of IBD patients. DUOX2 deficient mice replicated increased IL17C induction in the intestine, with outlier high Il17c expression linked to the mucosal expansion of specific Proteobacteria pathobionts. Integrated microbiota/host gene expression analyses in IBD patients corroborated IL17C as a marker for epithelial activation by gram-negative bacteria. Finally, the impact of DUOX2 variants on IL17C induction provided a rationale for variant stratification in case-control studies that substantiated DUOX2 as an IBD risk gene (pooled OR = 1.54 [95% CI 1.09-2.18]; P = 7.1e-4). Thus, our study identifies an association of deleterious DUOX2 variants with a preclinical hallmark of disturbed microbiota-immune homeostasis that appears to precede the manifestation of IBD.
Helmut Grasberger, Andrew T. Magis, Elisa Sheng, Matthew P. Conomos, Min Zhang, Lea S. Garzotto, Guoqing Hou, Shrinivas Bishu, Hiroko Nagao-Kitamoto, Mohamad El-Zataari, Sho Kitamoto, Nobuhiko Kamada, Ryan Stidham, Yasutada Akiba, Jonathan Kaunitz, Yael Haberman, Subra Kugathasan, Lee A. Denson, Gilbert S. Omenn, John Y. Kao
JCI This Month is a digest of the research, reviews, and other features published each month.
Diabetes results from a disturbance in regulating blood sugar. In type 1 diabetes, an autoimmune response triggers the destruction of pancreatic beta cells, which produce insulin that controls glucose uptake in cells, whereas type 2 diabetes is caused by impairments in making or responding to insulin. The discovery of insulin in 1921 led to lifesaving therapy for type 1 diabetes and ushered in the era of modern medicine based on understanding the molecular basis of disease. Curated by JCI’s editor in chief, Rexford S. Ahima, the reviews in this series explore a wide range of topics in diabetes, from insulin’s discovery, insulin secretion and signaling, type 1 diabetes, monogenic diabetes, and insulin resistance syndromes, as well as pharmacological and dietary treatment options for type 2 diabetes. Cumulatively, these reviews highlight the genetic and molecular mechanisms underlying diabetes pathogenesis and discuss existing and potential new therapeutic approaches to treat and manage diabetes.