This issue marks the transition of JCI Insight’s Editorial Board to a new team led by Oliver Eickelberg and colleagues at the University of Pittsburgh. In his inaugural editorial, Dr. Eickelberg shares his vision for the next 5 years and plans to take the journal to even farther reaches.
Image credit: Oliver Eickelberg
Immune cell mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4+T cells in normal or diabetic wound repair, however, the imbalance of CD4+TH17/Treg cells has been found to promote inflammation in other diabetic tissues. Here, using human tissue and murine transgenic models, we identified that the histone methyltransferase MLL1 directly regulates the TH17 transcription factor RORγ via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Further, we found that Notch receptor signaling regulates CD4+TH cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4+T cells resulted in the loss of CD4+TH cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling were upregulated in wound CD4+TH cells, driving CD4+ T cells towards the TH17 cell phenotype. Treatment of diabetic wound CD4T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4+TH17 cells and IL17A. This is the first study to identify the MLL1-mediated mechanisms responsible for regulating the TH17/Treg balance in normal and diabetic wounds and define the complex role of Notch signaling in CD4+T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4+TH cells may decrease pathologic inflammation through regulation of CD4+T cell differentiation.
William J. Melvin, Tyler M. Bauer, Kevin D. Magnum, Christopher O. Audu, James Shadiow, Emily Barrett, Amrita Joshi, Jadie Y. Moon, Rachel Bogel, Purba Mazumder, Sonya J. Wolf, Steven Kunkel, Johann E. Gudjonsson, Frank M. Davis, Katherine A. Gallagher
Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR’s pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 cell cycle arrest. We also found that AZD6738 increased the number of micronuclei after exposure to radiotherapy. We found that combining radiation with AZD6738 led to tumor growth delay and prolonged survival relative to radiation alone in a breast cancer model. Combining AZD6738 with photons or protons also led to increased macrophage infiltration at the tumor microenvironment. These results provide a rationale for further investigation of ATR inhibition in combination with radiotherapy and with other agents such as immune checkpoint blockade.
Scott J. Bright, Mandira Manandhar, David B. Flint, Rishab Kolachina, Mariam Ben Kacem, David K.J. Martinus, Broderick X. Turner, Ilsa Qureshi, Conor H. McFadden, Poliana Camila Marinello, Simona F. Shaitelman, Gabriel O. Sawakuchi
Post-transplantation, T helper 1 (Th1)-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ dendritic cells (DC2) and CD103+ dendritic cells (DC1). This interaction necessitates further investigation in context of transplant immunity. We use a well-established pre-clinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+DC1 demonstrate a tolerogenic phenotype that modulate the immunogenic capacity of CD11b+DC2 primarily mediated by IL-10, suppressing alloreactive CD4+Th1 cells via the PD-L1/PD-1 pathway, and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGFβ1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+Th1 cells induces migratory CD103+DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers including αvβ8 integrin and IL-10 and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex-vivo induced tolerogenic CD103+DC1(iDC1) effectively inhibits Th1 polarization and preserves the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+DC1 in modulating host alloimmune responses.
Tomas Blanco, Hayate Nakagawa, Aytan Musayeva, Mark Krauthammer, Rohan Bir Singh, Akitomo Narimatsu, Hongyan Ge, Sara I. Shoushtari, Reza Dana
Our objective was to interrogate infant mesenchymal stem cell (MSC) lipid metabolism and gestational exposures that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n=16) or normal-weight (n=15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24h excess fatty acid, 24hFA). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, tumor necrosis factor-α, high density lipoprotein- and total- cholesterol in fasting blood from mid- and late-gestation (~17, ~27wks). We measured child adiposity at birth (n=29), 4-6m (n=29), and 4-6y (n=13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster-2. All Clusters increased acylcarnitines and TAGs with 24hFA, though Cluster-2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC Clusters and child adiposity at 4-6y (both highest in Cluster-3). Our data supports that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, though validation with larger longitudinal samples is warranted.
Lauren E. Gyllenhammer, Vincent Zaegel, Allison M. Duensing, Manoel Lixandrao, Dana Dabelea, Bryan C. Bergman, Kristen E. Boyle
The prevalence of chronic kidney diseases (CKD) varies by race due to genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asians, alters the enzyme's function in detoxifying alcohol-derived aldehydes, impacting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicates that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein, an aldehyde metabolized by ALDH2, and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys knock-in mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and co-activation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduces acrolein and mitigates fibrosis in both wild-type and Glu504Lys knock-in mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.
Szu-yuan Li, Ming-Tsun Tsai, Yu-Ming Kuo, Hui-Min Yang, Zhen-Jie Tong, Hsiao-Wei Cheng, Chih-Ching Lin, Hsiang-Tsui Wang