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DC inhibitory receptor (DCIR) is a C-type lectin receptor selectively expressed on myeloid cells, including monocytes, macrophages, DCs, and neutrophils. Its role in immune regulation has been implicated in murine models and human genome-wide association studies, suggesting defective DCIR function associates with increased susceptibility to autoimmune diseases such as rheumatoid arthritis, lupus, and Sjögren’s syndrome. However, little is known about the mechanisms underlying DCIR activation to dampen inflammation. Here, we developed anti-DCIR agonistic antibodies that promote phosphorylation on DCIR’s immunoreceptor tyrosine-based inhibitory motifs and recruitment of SH2 containing protein tyrosine phosphatase-2 for reducing inflammation. We also explored the inflammation resolution by depleting DCIR+ cells with antibodies. Utilizing a human DCIR–knock-in mouse model, we validated the antiinflammatory properties of the agonistic anti-DCIR antibody in experimental peritonitis and colitis. These findings provide critical evidence for targeting DCIR to develop transformative therapies for inflammatory diseases.
Liang Chen, Suresh Patil, Jeffrey Barbon, James Waire, Stephen Laroux, Donna McCarthy, Mishra Pratibha, Suju Zhong, Feng Dong, Karin Orsi, Gunarso Nguyen, Yingli Yang, Nancy Crosbie, Eric Dominguez, Arun Deora, Geertruida Veldman, Susan Westmoreland, Liang Jin, Timothy Radstake, Kevin White, Hsi-Ju Wei
Total views: 1760
Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.
Takatoshi Enomoto, Yuya Shirai, Yoshito Takeda, Ryuya Edahiro, Shigeyuki Shichino, Mana Nakayama, Miho Takahashi-Itoh, Yoshimi Noda, Yuichi Adachi, Takahiro Kawasaki, Taro Koba, Yu Futami, Moto Yaga, Yuki Hosono, Hanako Yoshimura, Saori Amiya, Reina Hara, Makoto Yamamoto, Daisuke Nakatsubo, Yasuhiko Suga, Maiko Naito, Kentaro Masuhiro, Haruhiko Hirata, Kota Iwahori, Izumi Nagatomo, Kotaro Miyake, Shohei Koyama, Kiyoharu Fukushima, Takayuki Shiroyama, Yujiro Naito, Shinji Futami, Yayoi Natsume-Kitatani, Satoshi Nojima, Masahiro Yanagawa, Yasushi Shintani, Mari Nogami-Itoh, Kenji Mizuguchi, Jun Adachi, Takeshi Tomonaga, Yoshikazu Inoue, Atsushi Kumanogoh
Total views: 1528
Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for the presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix (ECM) organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location. We found that the relationships between genetic and TME diversity are different in primary and matched recurrent tumors. Interestingly, the texture of the ECM, identified by label-free reflectance imaging, was predictive of single-cell genetic traits present in the tissue. Moreover, reflectance of ECM revealed structured organization of the perivascular niche in recurrent GBM, enriched in immunosuppressive macrophages. Single-cell spatial transcriptomics further confirmed the presence of the niche-specific macrophage populations and identified interactions between endothelial cells, perivascular fibroblasts, and immunosuppressive macrophages. Our results underscore the importance of GBM tissue organization in tumor evolution and highlight genetic and spatial dependencies.
Ugoma Onubogu, Chandler D. Gatenbee, Sandhya Prabhakaran, Kelsey L. Wolfe, Benjamin Oakes, Roberto Salatino, Rachael Vaubel, Oszkar Szentirmai, Alexander R.A. Anderson, Michalina Janiszewska
Total views: 1475
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin–treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts “immune desert phenotypes” toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Lisa A. Ridnour, Robert Y.S. Cheng, Noemi Kedei, Veena Somasundaram, Dibyangana D. Bhattacharyya, Debashree Basudhar, Adelaide L. Wink, Abigail J. Walke, Caleb Kim, William F. Heinz, Elijah F. Edmondson, Donna O. Butcher, Andrew C. Warner, Tiffany H. Dorsey, Milind Pore, Robert J. Kinders, Stanley Lipkowitz, Richard J. Bryant, Jens Rittscher, Stephen T.C. Wong, Stephen M. Hewitt, Jenny C. Chang, Aliaa Shalaby, Grace M. Callagy, Sharon A. Glynn, Stefan Ambs, Stephen K. Anderson, Daniel W. McVicar, Stephen J. Lockett, David A. Wink
Total views: 1381
Clinical trials delivering high doses of adeno-associated viruses (AAVs) expressing truncated dystrophin molecules (microdystrophins) are underway for Duchenne muscular dystrophy (DMD). We examined the efficiency and efficacy of this strategy with 4 microdystrophin constructs (3 in clinical trials and a variant of the largest clinical construct), in a severe mouse model of DMD, using AAV doses comparable with those in clinical trials. We achieved high levels of microdystrophin expression in striated muscles with cardiac expression approximately 10-fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of skeletal muscle disease was observed. Surprisingly, a lethal acceleration of cardiac disease occurred with 2 of the microdystrophins. The detrimental cardiac effect appears to be caused by variable competition (dependent on microdystrophin design and expression level) between microdystrophin and utrophin at the cardiomyocyte membrane. There may also be a contribution from an overloading of protein degradation. The significance of these observations for patients currently being treated with AAV-microdystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown. However, these findings suggest that microdystrophin treatments need to avoid excessively high levels of expression in the heart and that cardiac function should be carefully monitored in these patients.
Cora C. Hart, Young il Lee, Jun Xie, Guangping Gao, Brian L. Lin, David W. Hammers, H. Lee Sweeney
Total views: 1337
Rheumatoid arthritis (RA) management lean toward achieving remission or low-disease activity. In this study, we conducted single-cell RNA sequencing (scRNAseq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 RA patients and 18 matched controls, accounting for age, sex, race, and ethnicity), to identify disease-relevant cell subsets and cell type-specific signatures associated with disease activity. Our analysis revealed 18 distinct PBMC subsets, including an IFITM3 overexpressing Interferon-activated (IFN-activated) monocyte subset. We observed an increase in CD4+ T effector memory cells in patients with moderate to high disease activity (DAS28-CRP ≥ 3.2), and a decrease in non-classical monocytes in patients with low disease activity or remission (DAS28-CRP < 3.2). Pseudobulk analysis by cell type identified 168 differentially expressed genes between RA and matched controls, with a downregulation of pro-inflammatory genes in the gamma-delta T cells subset, alteration of genes associated with RA predisposition in the IFN-activated subset, and non-classical monocytes. Additionally, we identified a gene signature associated with moderate-high disease activity, characterized by upregulation of pro-inflammatory genes such as TNF, JUN, EGR1, IFIT2, MAFB, G0S2, and downregulation of genes including HLA-DQB1, HLA-DRB5, TNFSF13B. Notably, cell-cell communication analysis revealed an upregulation of signaling pathways, including VISTA, in both moderate-high and remission-low disease activity contexts. Our findings provide valuable insights into the systemic cellular and molecular mechanisms underlying RA disease activity.
Marie Binvignat, Brenda Y. Miao, Camilla Wibrand, Monica M. Yang, Dmitry Rychkov, Emily Flynn, Joanne Nititham, Whitney Tamaki, Umair Khan, Alexander Carvidi, Melissa Krueger, Erene C. Niemi, Yang Sun, Gabriela K. Fragiadakis, Jérémie Sellam, Encarnita Mariotti-Ferrandiz, David Klatzmann, Andrew J. Gross, Chun Jimmie Ye, Atul J. Butte, Lindsey A. Criswell, Mary C. Nakamura, Marina Sirota
Total views: 1294
Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune-mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single-cell RNA-Seq and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell–mediated depletion of B cells in patients with SLE. The resulting data sets not only confirm a selective CAR T cell–mediated reset of the B cell response but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type I IFN signaling. Our current data, thus, provide evidence for a causal relationship between the B cell response and the increased IFN signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans.
Artur Wilhelm, David Chambers, Fabian Müller, Aline Bozec, Ricardo Grieshaber-Bouyer, Thomas Winkler, Dimitrios Mougiakakos, Andreas Mackensen, Georg Schett, Gerhard Krönke
Total views: 1272
Recently, skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs), but their function in connection with linear bone growth remains unknown. Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.
Dana Trompet, Anastasiia D. Kurenkova, Baoyi Zhou, Lei Li, Ostap Dregval, Anna P. Usanova, Tsz Long Chu, Alexandra Are, Andrei A. Nedorubov, Maria Kasper, Andrei S. Chagin
Total views: 1271
The regulated glycosylation of the proteome has widespread effects on biological processes that cancer cells can exploit. Expression of N-acetylglucosaminyltransferase V (encoded by Mgat5 or GnT-V), which catalyzes the addition of β1,6-linked N-acetylglucosamine to form complex N-glycans, has been linked to tumor growth and metastasis across tumor types. Using a panel of murine pancreatic ductal adenocarcinoma (PDAC) clonal cell lines that recapitulate the immune heterogeneity of PDAC, we found that Mgat5 is required for tumor growth in vivo but not in vitro. Loss of Mgat5 results in tumor clearance that is dependent on T cells and dendritic cells, with NK cells playing an early role. Analysis of extrinsic cell death pathways revealed Mgat5-deficient cells have increased sensitivity to cell death mediated by the TNF superfamily, a property that was shared with other non-PDAC Mgat5-deficient cell lines. Finally, Mgat5 knockout in an immunotherapy-resistant PDAC line significantly decreased tumor growth and increased survival upon immune checkpoint blockade. These findings demonstrate a role for N-glycosylation in regulating the sensitivity of cancer cells to T cell killing through classical cell death pathways.
Erin E. Hollander, Rosemary E. Flock, Jayne C. McDevitt, William P. Vostrejs, Sydney L. Campbell, Margo I. Orlen, Samantha B. Kemp, Benjamin M. Kahn, Kathryn E. Wellen, Il-Kyu Kim, Ben Z. Stanger
Total views: 1224
Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.
Manjula Darshi, Luxcia Kugathasan, Soumya Maity, Vikas S. Sridhar, Roman Fernandez, Christine P. Limonte, Brian I. Grajeda, Afaf Saliba, Guanshi Zhang, Viktor R. Drel, Jiwan J. Kim, Richard Montellano, Jana Tumova, Daniel Montemayor, Zhu Wang, Jian-Jun Liu, Jiexun Wang, Bruce A. Perkins, Yuliya Lytvyn, Loki Natarajan, Su Chi Lim, Harold Feldman, Robert Toto, John R. Sedor, Jiten Patel, Sushrut S. Waikar, Julia Brown, Yahya Osman, Jiang He, Jing Chen, W. Brian Reeves, Ian H. de Boer, Sourav Roy, Volker Vallon, Stein Hallan, Jonathan A.L. Gelfond, David Z.I. Cherney, Kumar Sharma, for the Kidney Precision Medicine Project, and the CRIC Study Investigators
Total views: 1179