Conventional memory CD8+ T cells and mucosal-associated invariant T cells (MAIT cells) are found in blood, liver, and mucosal tissues and have similar effector potential following activation, specifically expression of IFN-γ and granzyme B. To better understand each subset’s unique contributions to immunity and pathology, we interrogated inflammation- and TCR-driven activation requirements using human memory CD8+ T and MAIT cells isolated from blood and mucosal tissue biopsies in ex vivo functional assays and single cell gene expression experiments. We found that MAIT cells had a robust IFN-γ and granzyme B response to inflammatory signals but limited responsiveness when stimulated directly via their TCR. Importantly, this is not due to an overall hyporesponsiveness to TCR signals. When delivered together, TCR and inflammatory signals synergize to elicit potent effector function in MAIT cells. This unique control of effector function allows MAIT cells to respond to the same TCR signal in a dichotomous and situation-specific manner. We propose that this could serve to prevent responses to antigen in noninflamed healthy mucosal tissue, while maintaining responsiveness and great sensitivity to inflammation-eliciting infections. We discuss the implications of these findings in context of inflammation-inducing damage to tissues such as BM transplant conditioning or HIV infection.
Chloe K. Slichter, Andrew McDavid, Hannah W. Miller, Greg Finak, Brenda J. Seymour, John P. McNevin, Gabriela Diaz, Julie L. Czartoski, M. Juliana McElrath, Raphael Gottardo, Martin Prlic
Pancreatic ductal adenocarcinoma (Pdac) is a malignancy with a poor prognosis due to difficulties in early detection. Although promising biomarkers are increasingly reported, such methods are not yet easy to apply clinically, mainly due to their low reproducibility or technical difficulties. In this study, we developed a convenient and sensitive method for quantifying aberrantly expressed satellite repeat RNAs in sera, which can be used to efficiently detect patients with Pdac. Here, we introduce a Tandem Repeat Amplification by nuclease Protection (TRAP) method combined with droplet digital PCR (ddPCR) to detect human satellite II (HSATII) RNAs, which are specifically expressed in human Pdacs at greater levels than normal tissues but are difficult to measure due to their repetitive sequences and irregularities. HSATII RNA core sequence levels in sera were significantly higher in Pdac patients compared with noncancer patients (median copy number: 14.75 and 3.17 per μl in the training set and 17.35 and 2.9 in the validation set, respectively). In addition, patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous lesion of Pdac, could also be efficiently detected. This method can be routinely applied to screen patients with Pdac and high-risk patients, facilitating the development of preventive medicine for this disease.
Takahiro Kishikawa, Motoyuki Otsuka, Takeshi Yoshikawa, Motoko Ohno, Keisuke Yamamoto, Natsuyo Yamamoto, Ai Kotani, Kazuhiko Koike
Immune-suppressed organ transplant recipients (OTRs) can develop catastrophic squamous cell carcinoma (SCC), characterized by multiple primary tumors, extensive body surface area involvement, or metastases. There are currently no curative systemic therapies available. We previously showed that IL-22 enhances SCC proliferation. Herein, we examined links between cyclosporine (CSA), IL-22, and SCC in patients, cell lines, and mice with UV light–induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. We found that CSA drives T cell polarization toward IL-22–producing T22 cells, and CSA treatment increased IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1. CSA potentiated rescue by IL-22 of serum-starved SCC cells; treatment of SCC cells with IL-22 and CSA increased both their migratory and invasive capacity. In a UV-induced model of SCC in SKH-1 immunocompetent mice, treatment with anti–IL-22 antibody reduced tumor number and tumor burden. We found that catastrophic SCC in OTRs is associated with CSA use, which may be acting by favoring T22 polarization. Since anti–IL-22 antibody administration decreased tumor number and tumor burden in vivo, blockade of the IL-22 axis may be developed as a viable therapeutic option for catastrophic SCC.
Melody Abikhair, Hiroshi Mitsui, Valerie Yanofsky, Nazanin Roudiani, Channa Ovits, Teddy Bryan, Tatiana M. Oberyszyn, Kathleen L. Tober, Juana Gonzalez, James G. Krueger, Diane Felsen, John A. Carucci
Dopamine D2 receptor (DRD2) deficiency increases renal inflammation and blood pressure in mice. We show here that long-term renal-selective silencing of
Prasad R. Konkalmatt, Laureano D. Asico, Yanrong Zhang, Yu Yang, Cinthia Drachenberg, Xiaoxu Zheng, Fei Han, Pedro A. Jose, Ines Armando
Human induced pluripotent stem cells (iPSCs) can be derived from various types of somatic cells by transient overexpression of 4 Yamanaka factors (OCT4, SOX2, C-MYC, and KLF4). Patient-specific iPSC derivatives (e.g., neuronal, cardiac, hepatic, muscular, and endothelial cells [ECs]) hold great promise in drug discovery and regenerative medicine. In this study, we aimed to evaluate whether the cellular origin can affect the differentiation, in vivo behavior, and single-cell gene expression signatures of human iPSC–derived ECs. We derived human iPSCs from 3 types of somatic cells of the same individuals: fibroblasts (FB-iPSCs), ECs (EC-iPSCs), and cardiac progenitor cells (CPC-iPSCs). We then differentiated them into ECs by sequential administration of Activin, BMP4, bFGF, and VEGF. EC-iPSCs at early passage (10 < P < 20) showed higher EC differentiation propensity and gene expression of EC-specific markers (PECAM1 and NOS3) than FB-iPSCs and CPC-iPSCs. In vivo transplanted EC-iPSC–ECs were recovered with a higher percentage of CD31+ population and expressed higher EC-specific gene expression markers (PECAM1, KDR, and ICAM) as revealed by microfluidic single-cell quantitative PCR (qPCR). In vitro EC-iPSC–ECs maintained a higher CD31+ population than FB-iPSC–ECs and CPC-iPSC–ECs with long-term culturing and passaging. These results indicate that cellular origin may influence lineage differentiation propensity of human iPSCs; hence, the somatic memory carried by early passage iPSCs should be carefully considered before clinical translation.
Shijun Hu, Ming-Tao Zhao, Fereshteh Jahanbani, Ning-Yi Shao, Won Hee Lee, Haodong Chen, Michael P. Snyder, Joseph C. Wu
Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive collagen production and fibrogenesis. Apoptosis in lung epithelial cells is critical in IPF pathogenesis, as heightened loss of these cells promotes fibroblast activation and remodeling. Changes in glutathione redox status have been reported in IPF patients. S-glutathionylation, the conjugation of glutathione to reactive cysteines, is catalyzed in part by glutathione-
David H. McMillan, Jos L.J. van der Velden, Karolyn G. Lahue, Xi Qian, Robert W. Schneider, Martina S. Iberg, James D. Nolin, Sarah Abdalla, Dylan T. Casey, Kenneth D. Tew, Danyelle M. Townsend, Colin J. Henderson, C. Roland Wolf, Kelly J. Butnor, Douglas J. Taatjes, Ralph C. Budd, Charles G. Irvin, Albert van der Vliet, Stevenson Flemer, Vikas Anathy, Yvonne M.W. Janssen-Heininger
In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR) anion channel activity causes airway surface liquid (ASL) pH to become acidic, which impairs airway host defenses. One potential therapeutic approach is to correct the acidic pH in CF airways by aerosolizing HCO3– and/or nonbicarbonate pH buffers. Here, we show that raising ASL pH with inhaled HCO3– increased pH. However, the effect was transient, and pH returned to baseline values within 30 minutes. Tromethamine (Tham) is a buffer with a long serum half-life used as an i.v. formulation to treat metabolic acidosis. We found that Tham aerosols increased ASL pH in vivo for at least 2 hours and enhanced bacterial killing. Inhaled hypertonic saline (7% NaCl) is delivered to people with CF in an attempt to promote mucus clearance. Because an increased ionic strength inhibits ASL antimicrobial factors, we added Tham to hypertonic saline and applied it to CF sputum. We found that Tham alone and in combination with hypertonic saline increased pH and enhanced bacterial killing. These findings suggest that aerosolizing the HCO3–-independent buffer Tham, either alone or in combination with hypertonic saline, might be of therapeutic benefit in CF airway disease.
Mahmoud H. Abou Alaiwa, Janice L. Launspach, Kelsey A. Sheets, Jade A. Rivera, Nicholas D. Gansemer, Peter J. Taft, Peter S. Thorne, Michael J. Welsh, David A. Stoltz, Joseph Zabner
We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this effect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.
Niki D.J. Ubags, Renee D. Stapleton, Juanita H.J. Vernooy, Elianne Burg, Jenna Bement, Catherine M. Hayes, Sebastian Ventrone, Lennart Zabeau, Jan Tavernier, Matthew E. Poynter, Polly E. Parsons, Anne E. Dixon, Matthew J. Wargo, Benjamin Littenberg, Emiel F.M. Wouters, Benjamin T. Suratt
Although a close connection between uterine regeneration and successful pregnancy in both humans and mice has been consistently observed, its molecular basis remains unclear. We here established a mouse model of decellularized uterine matrix (DUM) transplantation. Resected mouse uteri were processed with SDS to make DUMs without any intact cells. DUMs were transplanted into the mouse uteri with artificially induced defects, and all the uterine layers were recovered at the DUM transplantation sites within a month. In the regenerated uteri, normal hormone responsiveness in early pregnancy was observed, suggesting the regeneration of functional uteri. Uterine epithelial cells rapidly migrated and formed a normal uterine epithelial layer within a week, indicating a robust epithelial-regenerating capacity. Stromal and myometrial regeneration occurred following epithelial regeneration. In ovariectomized mice, uterine regeneration of the DUM transplantation was similarly observed, suggesting that ovarian hormones are not essential for this regeneration process. Importantly, the regenerating epithelium around the DUM demonstrated heightened STAT3 phosphorylation and cell proliferation, which was suppressed in uteri of
Takehiro Hiraoka, Yasushi Hirota, Tomoko Saito-Fujita, Mitsunori Matsuo, Mahiro Egashira, Leona Matsumoto, Hirofumi Haraguchi, Sudhansu K. Dey, Katsuko S. Furukawa, Tomoyuki Fujii, Yutaka Osuga
Pulmonary arterial (PA) stiffness is associated with increased mortality in patients with pulmonary hypertension (PH); however, the role of PA stiffening in the pathogenesis of PH remains elusive. Here, we show that distal vascular matrix stiffening is an early mechanobiological regulator of experimental PH. We identify cyclooxygenase-2 (COX-2) suppression and corresponding reduction in prostaglandin production as pivotal regulators of stiffness-dependent vascular cell activation. Atomic force microscopy microindentation demonstrated early PA stiffening in experimental PH and human lung tissue. Pulmonary artery smooth muscle cells (PASMC) grown on substrates with the stiffness of remodeled PAs showed increased proliferation, decreased apoptosis, exaggerated contraction, enhanced matrix deposition, and reduced COX-2–derived prostanoid production compared with cells grown on substrates approximating normal PA stiffness. Treatment with a prostaglandin I2 analog abrogated monocrotaline-induced PA stiffening and attenuated stiffness-dependent increases in proliferation, matrix deposition, and contraction in PASMC. Our results suggest a pivotal role for early PA stiffening in PH and demonstrate the therapeutic potential of interrupting mechanobiological feedback amplification of vascular remodeling in experimental PH.
Fei Liu, Christina Mallarino Haeger, Paul B. Dieffenbach, Delphine Sicard, Izabela Chrobak, Anna Maria F. Coronata, Margarita M. Suárez Velandia, Sally Vitali, Romain A. Colas, Paul C. Norris, Aleksandar Marinković, Xiaoli Liu, Jun Ma, Chase D. Rose, Seon-Jin Lee, Suzy A.A. Comhair, Serpil C. Erzurum, Jacob D. McDonald, Charles N. Serhan, Stephen R. Walsh, Daniel J. Tschumperlin, Laura E. Fredenburgh
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