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3. Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation

Author

Zhang, Tao, Xu, Daichao, Liu, Jianping, Wang, Min, Duan, Li-Juan, Liu, Min, Meng, Huyan, Zhuang, Yuan, Wang, Huibing, Wang, Yingnan, Lv, Mingming, Zhang, Zhengyi, Hu, Jia, Shi, Linyu, Guo, Rui, Xie, Xingxing, Liu, Hui, Erickson, Emily, Wang, Yaru, Yu, Wenyu, Dang, Fabin, Guan, Dongxian, Jiang, Cong, Dai, Xiaoming, Inuzuka, Hiroyuki, Yan, Peiqiang, Wang, Jingchao, Babuta, Mrigya, Lian, Gewei, Tu, Zhenbo, Miao, Ji, Szabo, Gyongyi, Fong, Guo-Hua, Karnoub, Antoine E., Lee, Yu-Ru, Pan, Lifeng, Kaelin, Jr., William G., Yuan, Junying, and Wei, Wenyi

Published
2023
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4. Randomized trial of anakinra plus zinc vs. prednisone for severe alcohol-associated hepatitis

Author

Chalasani, Naga, Patidar, Kavish R., Vuppalanchi, Raj, Samala, Niha, Yoder, Lindsey, Nephew, Lauren, Shah, Vijay H., Simonetto, Douglas A., Kamath, Patrick, Vargas, Hugo E., Yang, Liu, Dasarathy, Srinivasan, Welch, Nicole, Bellar, Annette, Attaway, Amy, Dasarathy, Jaividhya, Growley, Ashley, Streem, David, Nagy, Laura E., Mitchell, Mack C., Herlong, H. Franklin, Kerr, Thomas, Cotter, Thomas, Sanyal, Arun, O'Connor, Sara, Luketic, Velimir, Asgharpour, Amon, Taylor, Stephanie, McClain, Craig J., Vatsalya, Vatsalya, Jophlin, Loretta, Cave, Matt, Jha, Suman Kumar, Marsano, Luis, Barve, Ashutosh, Frimodig, Jane, Bataller, Ramon, Ravi, Samhita, Behari, Jaideep, Shivanekar, Sharvari, Novelli, Paula, Duarte-Rojo, Andres, Jonassaint, Naudia, Szabo, Gyongyi, Curry, Jiang, Zhenghui G., Agarwal, Ushma, Hazel, Mia, Schnabl, Bernd, Gawrieh, Samer, Tu, Wanzhu, Kamath, Patrick S., Chalasani, Naga P., Tang, Qing, Radaeva, Svetlana, Barton, Bruce, and Sanyal, Arun J.

Published
2024
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5. Increased microRNA-155 expression in the serum and peripheral monocytes in chronic HCV infection

Author

Bala Shashi, Tilahun Yaphet, Taha Odette, Alao Hawau, Kodys Karen, Catalano Donna, and Szabo Gyongyi

Subjects
Biomarker, MiR-122, MiR-155, MiR-125b, ALT, Inflammation, Medicine
Abstract

Abstract Background Hepatitis C Virus (HCV), a single stranded RNA virus, affects millions of people worldwide and leads to chronic infection characterized by chronic inflammation in the liver and in peripheral immune cells. Chronic liver inflammation leads to progressive liver damage. MicroRNAs (miRNA) regulate inflammation (miR-155, -146a and -125b) as well as hepatocyte function (miR-122). Methods Here we hypothesized that microRNAs are dysregulated in chronic HCV infection. We examined miRNAs in the circulation and in peripheral monocytes of patients with chronic HCV infection to evaluate if specific miRNA expression correlated with HCV infection. Results We found that monocytes from chronic HCV infected treatment-naïve (cHCV) but not treatment responder patients showed increased expression of miR-155, a positive regulator of TNFα, and had increased TNFα production compared to monocytes of normal controls. After LPS stimulation, miR-155 levels were higher in monocytes from cHCV patients compared to controls. MiR-125b, which has negative regulatory effects on inflammation, was decreased in cHCV monocytes compared to controls. Stimulation of normal monocytes with TLR4 and TLR8 ligands or HCV core, NS3 and NS5 recombinant proteins induced a robust increase in both miR-155 expression and TNFα production identifying potential mechanisms for in vivo induction of miR-155. Furthermore, we found increased serum miR-155 levels in HCV patients compared to controls. Serum miR-125b and miR-146a levels were also increased in HCV patients. Serum levels of miR-122 were elevated in cHCV patients and correlated with increased ALT and AST levels and serum miR-155 levels. Conclusion In conclusion, our novel data demonstrate that miR-155, a positive regulator of inflammation, is upregulated both in monocytes and in the serum of patients with chronic HCV infection. Our study suggests that HCV core, NS3, and NS5 proteins or TLR4 and TLR8 ligands can mediate increased miR-155 and TNFα production in chronic HCV infection. The positive correlation between serum miR-155 and miR-122 increase in cHCV may be an indicator of inflammation-induced hepatocyte damage.

Published
2012
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6. Inhibition of TLR8- and TLR4-induced Type I IFN induction by alcohol is different from its effects on inflammatory cytokine production in monocytes

Author

Kodys Karen, Bala Shashi, Pang Maoyin, Catalano Donna, and Szabo Gyongyi

Subjects
Acute, chronic, alcohol, IFNβ, IL-10, TNF alpha, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Prolonged alcohol consumption is a significant co-factor in the progression of chronic viral infections including hepatitis C and HIV, which are both single-stranded RNA viruses. Toll like receptor 8 (TLR8), a pattern recognition receptor expressed in monocytes, senses viral single stranded RNA as a danger signal and leads to the induction of Type I interferon (IFN) as well as the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha). Lipopolysaccharide (LPS), a Toll like receptor 4 (TLR4) ligand, was shown to affect inflammatory cell activation after alcohol consumption and in HIV and HCV infections. Here we hypothesized that alcohol exposure modulates TLR8- and TLR4-ligand-induced monocyte activation and affects both type I IFN and inflammatory cytokine induction. Results The TLR8 ligand, CL075, as well as the TLR4 ligand, LPS, resulted in a significant induction of TNF alpha both at the mRNA and protein levels in human monocytes. We found that both acute and prolonged alcohol treatment resulted in inhibition of type I IFN induction by either TLR8 or TLR4 ligands in human monocytes at the protein and mRNA levels. In contrast to Type I IFN production, the effects of acute and prolonged alcohol were different on inflammatory cytokine activation after TLR8 or TLR4 ligand stimulation. Acute alcohol inhibited TLR8- or TLR4-induced TNF alpha protein and mRNA induction while it augmented IL-10 production in monocytes. In contrast, prolonged alcohol treatment augmented TNF alpha without affecting IL-10 production significantly in response to either TLR8 or TLR4 ligand stimulation. Conclusions These novel results suggest first, that alcohol has a profound inhibitory effect on Type I IFN induction regardless of intracellular (TLR8) or cell surface-derived (TLR4) danger signals. Second, both acute and prolonged alcohol exposure can inhibit antiviral Type I IFN pathway activation. Third, the opposite effects of acute (inhibitory) and prolonged alcohol (augmentation) treatment on pro-inflammatory cytokine activation extend to TLR8-induced signals beyond the previously shown TLR4/LPS pathway.

Published
2011
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11. Provider Attitudes and Practices for Alcohol Screening, Treatment, and Education in Patients With Liver Disease: A Survey From the American Association for the Study of Liver Diseases Alcohol-Associated Liver Disease Special Interest Group

Author

Im, Gene Y., Mellinger, Jessica L., Winters, Adam, Aby, Elizabeth S., Lominadze, Zurabi, Rice, John, Lucey, Michael R., Arab, Juan P., Goel, Aparna, Jophlin, Loretta L., Sherman, Courtney B., Parker, Richard, Chen, Po-Hung, Devuni, Deepika, Sidhu, Sandeep, Dunn, Winston, Szabo, Gyongyi, Singal, Ashwani K., and Shah, Vijay H.

Published
2021
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12. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets

Author

Delorey, Toni M., Ziegler, Carly G. K., Heimberg, Graham, Normand, Rachelly, Yang, Yiming, Segerstolpe, Åsa, Abbondanza, Domenic, Fleming, Stephen J., Subramanian, Ayshwarya, Montoro, Daniel T., Jagadeesh, Karthik A., Dey, Kushal K., Sen, Pritha, Slyper, Michal, Pita-Juárez, Yered H., Phillips, Devan, Biermann, Jana, Bloom-Ackermann, Zohar, Barkas, Nikolaos, Ganna, Andrea, Gomez, James, Melms, Johannes C., Katsyv, Igor, Normandin, Erica, Naderi, Pourya, Popov, Yury V., Raju, Siddharth S., Niezen, Sebastian, Tsai, Linus T.-Y., Siddle, Katherine J., Sud, Malika, Tran, Victoria M., Vellarikkal, Shamsudheen K., Wang, Yiping, Amir-Zilberstein, Liat, Atri, Deepak S., Beechem, Joseph, Brook, Olga R., Chen, Jonathan, Divakar, Prajan, Dorceus, Phylicia, Engreitz, Jesse M., Essene, Adam, Fitzgerald, Donna M., Fropf, Robin, Gazal, Steven, Gould, Joshua, Grzyb, John, Harvey, Tyler, Hecht, Jonathan, Hether, Tyler, Jané-Valbuena, Judit, Leney-Greene, Michael, Ma, Hui, McCabe, Cristin, McLoughlin, Daniel E., Miller, Eric M., Muus, Christoph, Niemi, Mari, Padera, Robert, Pan, Liuliu, Pant, Deepti, Pe’er, Carmel, Pfiffner-Borges, Jenna, Pinto, Christopher J., Plaisted, Jacob, Reeves, Jason, Ross, Marty, Rudy, Melissa, Rueckert, Erroll H., Siciliano, Michelle, Sturm, Alexander, Todres, Ellen, Waghray, Avinash, Warren, Sarah, Zhang, Shuting, Zollinger, Daniel R., Cosimi, Lisa, Gupta, Rajat M., Hacohen, Nir, Hibshoosh, Hanina, Hide, Winston, Price, Alkes L., Rajagopal, Jayaraj, Tata, Purushothama Rao, Riedel, Stefan, Szabo, Gyongyi, Tickle, Timothy L., Ellinor, Patrick T., Hung, Deborah, Sabeti, Pardis C., Novak, Richard, Rogers, Robert, Ingber, Donald E., Jiang, Z. Gordon, Juric, Dejan, Babadi, Mehrtash, Farhi, Samouil L., Izar, Benjamin, Stone, James R., Vlachos, Ioannis S., Solomon, Isaac H., Ashenberg, Orr, Porter, Caroline B. M., Li, Bo, Shalek, Alex K., Villani, Alexandra-Chloé, Rozenblatt-Rosen, Orit, and Regev, Aviv

Published
2021
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13. In vivo Bruton's tyrosine kinase inhibition attenuates alcohol-associated liver disease by regulating CD84-mediated granulopoiesis.

Author

Nagesh, Prashanth Thevkar, Cho, Yeonhee, Zhuang, Yuan, Babuta, Mrigya, Ortega-Ribera, Marti, Joshi, Radhika, Brezani, Veronika, Patel, Arman, Datta, Aditi Ashish, Brezani, Viliam, Hsieh, Yun-Cheng, Ramos, Adriana, Mehta, Jeeval, Copeland, Christopher, Kanata, Eleni, Jiang, Zhenghui Gordon, Vlachos, Ioannis, Asara, John, and Szabo, Gyongyi

Subjects
BRUTON tyrosine kinase, BONE marrow, RNA sequencing, GENE expression, LABORATORY mice
Abstract

Severe alcohol-associated hepatitis (AH) is a life-threatening form of alcohol-associated liver disease. Liver neutrophil infiltration is a hallmark of AH, yet the effects of alcohol on neutrophil functions remain elusive. Identifying therapeutic targets to reduce neutrophil-mediated liver damage is essential. Bruton's tyrosine kinase (BTK) plays an important role in neutrophil development and function; however, the role of BTK in AH is unknown. Using RNA sequencing of circulating neutrophils, we found an increase in Btk expression (P = 0.05) and phosphorylated BTK (pBTK) in patients with AH compared with healthy controls. In vitro, physiologically relevant doses of alcohol resulted in a rapid, TLR4-mediated induction of pBTK in neutrophils. In a preclinical model of AH, administration of a small-molecule BTK inhibitor (evobrutinib) or myeloid-specific Btk knockout decreased proinflammatory cytokines and attenuated neutrophil-mediated liver damage. We found that pBTK was essential for alcohol-induced bone marrow granulopoiesis and liver neutrophil infiltration. In vivo, BTK inhibition or myeloid-specific Btk knockout reduced granulopoiesis, circulating neutrophils, liver neutrophil infiltration, and liver damage in a mouse model of AH. Mechanistically, using liquid chromatography–tandem mass spectrometry, we identified CD84 as a kinase target of BTK, which is involved in granulopoiesis. In vitro, CD84 promoted alcohol-induced interleukin-1β and tumor necrosis factor–α in primary human neutrophils, which was inhibited by CD84-blocking antibody treatment. Our findings define the role of BTK and CD84 in regulating neutrophil inflammation and granulopoiesis, with potential therapeutic implications in AH. Editor's summary: Alcoholic liver disease is uniquely characterized by the hepatic infiltration of neutrophils. Nagesh et al. now show that Bruton's tyrosine kinase (BTK) is involved in this altered neutrophil homeostasis. Studying mouse models of alcohol-associated hepatitis, they found that BTK directly interacted with CD84 to promote bone marrow granulopoiesis and the inflammatory neutrophil infiltration that drives subsequent liver injury, particularly after alcohol binge. Pharmacological BTK inhibition reduced proinflammatory cytokines and attenuated neutrophil-mediated liver damage in a mouse model of alcohol-associated hepatitis. BTK activation was also found to be increased in patients with alcohol-associated hepatitis, indicating translational relevance of the identified mechanism of alcohol-induced liver injury. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Published
2024
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15. Combined Insults of a MASH Diet and Alcohol Binges Activate Intercellular Communication and Neutrophil Recruitment via the NLRP3-IL-1β Axis in the Liver.

Author

Babuta, Mrigya, Nagesh, Prashanth Thevkar, Datta, Aditi Ashish, Remotti, Victoria, Zhuang, Yuan, Mehta, Jeeval, Lami, Francesca, Wang, Yanbo, and Szabo, Gyongyi

Subjects
NEUTROPHILS, LIVER, BINGE drinking, HEPATITIS, LIVER cells, LIVER regeneration, CELL communication
Abstract

Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol use on the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) remain unexplored. Here, we show that short-term feeding of a metabolic-dysfunction-associated steatohepatitis (MASH) diet plus daily acute alcohol binges for three days induce liver injury and activation of the NLRP3 inflammasome. We identify that a MASH diet plus acute alcohol binges promote liver inflammation via increased infiltration of monocyte-derived macrophages, neutrophil recruitment, and NET release in the liver. Our results suggest that both monocyte-derived macrophages and neutrophils are activated via NLRP3, while the administration of MCC950, an NLRP3 inhibitor, dampens these effects.In this study, we reveal important intercellular communication between hepatocytes and neutrophils. We discover that the MASH diet plus alcohol induces IL-1β via NLRP3 activation and that IL-1β acts on hepatocytes and promotes the production of CXCL1 and LCN2. In turn, the increase in these neutrophils recruits chemokines and causes further infiltration and activation of neutrophils in the liver. In vivo administration of the NLRP3 inhibitor, MCC950, improves the early phase of MetALD by preventing liver damage, steatosis, inflammation, and immune cells recruitment. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials

Author

Gadano, Adrian, Martins, Marcelo, Angus, Peter, Bate, John, Danta, Mark, George, Jacob, Hodge, Alexander, Kontorinis, Nickolas, Roberts, Stuart, Sanagapalli, Santosh, Skoien, Richard, Thompson, Alexander, Zekry, Amany, Stauber, Rudolf, Trauner, Michael, Moreno, Christophe, Reynaert, Hendrik, Verbeke, Len, Silva, Mario Reis Alvares da, Parise, Edison, Oliveira, Claudia Pinto Marques Souza de, Araujo, Roberta Chaves, Martinelli, Ana de Lourdes Candolo, Borman, Meredith, Chandok, Natasha, Elkhashab, Magdy, Fraser, Hughie, Kaita, Kelly, Ma, Mang, Marotta, Paul, Ramji, Alnoor, Tam, Edward, Yoshida, Eric, Swain, Mark, Sebastiani, Giada, Petrunia, Denis, Abergel, Armando, Anty, Rodolphe, Bourlière, Marc, Boursier, Jérôme, Bureau, Christophe, Castera, Laurent, Habersetzer, François, Hézode, Christophe, Ledinghen, Victor De, Leroy, Vincent, Loustaud-Ratti, Véronique, Mathurin, Philippe, Pol, Stanislas, Zoulim, Fabien, Hinrichsen, Holger, Ingiliz, Patrick, Lammert, Frank, Manns, Michael, Schattenberg, Jörn, Schiefke, Ingolf, Trautwein, Christian, Zeuzem, Stefan, Hui, Aric, Li, King-Kong, Wong, Vincent, Acharya, Subrat, Chowdhury, Abhijit, Duseja, Ajay, Kapoor, Dharmesh, Mukewar, Shrikant, Sarin, Shiv, Shah, Samir, Shalimar, Sood, Ajit, Tantry, BV, Ben-Ari, Ziv, Katchman, Helena, Safadi, Rifaat, Veitsman, Ella, Zuckerman, Eli, Brunetto, Maurizia, Lampertico, Pietro, Mangia, Alessandra, Akahane, Takemi, Akuta, Norio, Eguchi, Yuichiro, Fujiyama, Shigetoshi, Genda, Takuya, Hiasa, Yoichi, Ido, Akio, Ikeda, Fusao, Ikegami, Tadashi, Imajo, Kento, Itoh, Yoshito, Iwasa, Motoh, Karino, Yoshiyasu, Kato, Naoya, Kawaguchi, Takumi, Kawanaka, Miwa, Kido, Masahiro, Kobayashi, Tomoo, Kurosaki, Masayuki, Matsuzaki, Yasushi, Mita, Eiji, Mizukoshi, Eishiro, Nakahara, Takashi, Nomura, Hideyuki, Notsumata, Kazuo, Okanoue, Takeshi, Saito, Satoshi, Sakugawa, Hiroshi, Suzuki, Yoshiyuki, Takaguchi, Koichi, Takaki, Akinobu, Takashima, Tomoyuki, Tanaka, Saiyu, Tsuji, Keiji, Ueno, Yoshiyuki, Umemura, Takeji, Uto, Hirofumi, Yamashita, Nobuyuki, Yanase, Mikio, Yatsuhashi, Hiroshi, Yoneda, Masashi, Chan, Wah Kheong, Tan, Soek Siam, Garza, Laura Cisneros, Ladron De Guevara Cetina, Alma, Angeles, Rocio Guadalupe Vargas, Silva, Francisca Martinez, Van Erpecum, Karel, Orr, David, Jabłkowski, Maciej, Jaroszewicz, Jerzy, Ramos, Jose, Ahmed, Taufique, Ang, Tiing, Dan, Yock young, Goh, Boon Bee, Kaliyaperumal, Kalaiyarasi, Yip, Cherng Hann, Baik, Soon Koo, Jang, Byoung Kuk, Jun, Dae Won, Kim, Won, Kim, Hyung Joon, Kim, Ji Hoon, Lee, Kwan Sik, Lee, Chun Kyon, Lim, Young-Suk, Park, Jun Yong, Tak, Won Young, Augustin, Salvador, Perez, Salvador Benlloch, Caballeria, Juan, Luis, Jose, Panero, Calleja, Rodríguez, Jose Carrión, Garcia, Javier Crespo, Samaniego, Javier Garcia, Gibert, Pere Ginès, Prieto, Martin, Gomez, Manuel Romero, Turnes, Juan, Dufour, Jean-Francois, Moriggia, Alberto, Sheen, I-Shyan, Kao, Jia-Horng, Cheng, Pin-Nan, Huang, Jee-Fu, Yang, Sheng-Shun, Su, Wei-Wen, Chen, Chi-Yi, Chien, Rong-Nan, Lo, Gin-Ho, Chu, Chi-Jen, Wang, Horng-Yuan, Hu, Jui-Ting, Huang, Yi Wen, Agarwal, Kosh, Allison, Michael, Anstee, Quentin, Austin, Andrew, Fowell, Andrew, Ch'ng, Chin Lye, Manousou, Pinelopi, Newsome, Philip, Ryder, Stephen, Shankar, Arun, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Alam, Imtiaz, Alba, Laura, Alkhouri, Naim, Allen, Alina, Aqel, Bashar, Balart, Luis, Barritt, A. Sidney, IV, Behari, Jaideep, Bennett, Michael, Bernstein, David, Bhandari, Bal Raj, Bonacini, Maurizio, Borg, Brian, Brown, Kimberly, Bzowej, Natalie, Caldwell, Stephen, Chami, Tawfik, Coates, Allan, Cueli, Adolfo, Davis, Mitchell, deLemos, Andrew, Desai, Archita, Dunn, Winston, Ferreira, Nelson, Fine, Michael, Firpi-Morell, Roberto, Freedland, Curtis, Freilich, Bradley, Fuchs, Michael, Galambos, Michael, Gallegos-Orozco, Juan, Galler, Greg, Ghali, Maged, Ghalib, Reem, Gill, Satinder, Gillis, Marcum, Gilroy, Richard, Gordon, Stuart, Gunn, Nadege, Halegoua-DeMarzio, Dina, Hassan, Mohamed, Hassanein, Tarek, Herring, Robert, Jr., Hong, John, Huang, Jonathan, Kabler, Heidi, Kayali, Zeid, Knapple, Whitfield, Kolli, Geetha, Kowdley, Kris, Krause, Richard, Lawitz, Eric, Lidofsky, Steven, Lim, Joseph, Lipkis, Donald, Loomba, Rohit, Mahgoub, Amar, Malespin, Miguel, Manch, Richard, Mannis, Steven, Manos, Paul, McDonald, Thomas, McKenzie, Mark, Mena, Edward, Merriman, Raphael, Moehlen, Martin William, Montgomery, Richard, Murphy, Robert, Natarajan, Yamini, Neff, Guy, Noureddin, Mazen, Ortiz-Lasanta, Grisell, Pagadala, Mangesh, Patel, Keyur, Patton, Heather, Peyton, Adam, Pimstone, Neville, Poulos, John, Pound, David, Pyrsopoulos, Nikolaos, Rafiq, Nila, Ravendhran, Natarajan, Ravinuthala, Ravi, Reddy, K. Rajendar, Reindollar, Robert, Reynolds, Justin, Rinella, Mary, Rizvi, Syed, Rockey, Don, Rodriguez-Perez, Federico, Ruane, Peter, Rubin, Raymond, Ryan, Michael, Saeian, Kia, Sanyal, Arun, Sarkar, Souvik, Scanga, Andrew, Schiff, Eugene, Schmidt, Warren, Schneider, Jeffrey, Sepe, Thomas, Shah, Dhiren, Shaikh, Obaid, Shankar, Uday, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shiffman, Mitchell, Siddique, Asma, Smith, Matthew, Suarez, Rosa, Talal, Andrew, Te, Helen, Tekola, Bezawit, Tetri, Brent, Thuluvath, Paul, Toro, Doris, Torres, Dawn, Trinh, Huy, Trotter, James, Vento, Angel, Vierling, John, Vuppalanchi, Raj, Waters, Michael, Weisberg, Ilan, Wieland, Amanda, Williams, Alonzo, Younes, Ziad, Adams, Leon, Harding, Damian, Hodge, Alex, Kontorinis, Nick, Strasser, Simone, Thompson, Alex, Horsmans, Yves, Steenkiste, Christophe Van, Bailey, Robert, Giard, Jeanne-Marie, Montano-Loza, Aldo, Puglia, Marco, Tsoi, Keith, Larrey, Dominique, Nguyen-Khac, Eric, Ratziu, Vlad, Spengler, Ulrich, Wiegand, Johannes, Hui, Aric Josun, Acharya, Subrat Kumar, Sarin, Shiv Kumar, Tantry, Vishwanath, Braun, Marius, Hazzan, Rawi, Lurie, Yoav, Colombo, Massimo, Fujii, Hideki, Hashimoto, Etsuko, Kato, Masaki, Ogawa, Koji, Takehara, Tetsuo, Tokushige, Katsutoshi, Garza, Laura Esthela Cisneros, Ladrón De Guevara, Alma Laura, Schultz, Michael, Janczewska, Ewa, Toro, Doris H., Jeong, Sook-Hyang, Kim, Yoon Jun, Lee, Jin-Woo, Ang, Tiing Leong, Bee, George Goh Boon, Benlloch, Salvador, Caballería, Juan, Calleja, José Luis, Rodríguez, Jose A. Carrión, Crespo, Javier, Diago, Moises, Fernandez-Rodriguez, Conrado, García-Samaniego, Javier, Ginès, Pere, Romero, Manuel, Dufour, Jean-François, Alazawi, William, Ch'ng, Chin-Lye, Forton, Daniel, Priest, Matthew, Sheridan, David, Ankoma-Sey, Victor, Balakrishnan, Maya, Bambha, Kiran, Barritt, A. Sidney, Bhandari, Bal, Brandman, Danielle, Chang, Charissa, Corey, Kathleen, Feldman, Michael, Gholam, Pierre, Goff, John, Marzio, Dina Halegoua-De, Harrison, Stephen, Hellstern, Paul, Jr., Herring, Robert, Iyer, Rajalakshmi, Jakiche, Antoine, Kohli, Anita, Krok, Karen, Kugelmas, Marcelo, Kumar, Sonal, Lai, Michelle, Mahmoud, Mitchell, Mantry, Parvez, Marsano, Luis, Nguyen, Tuan, Park, James, Patton, Heather M., Pockros, Paul, Reddy, Rajender, Rodriguez, Miguel, Sarles, Harry, Satapathy, Sanjaya, Sedghi, Shahriar, Shah, Nikunj, Sheikh, Muhammad Yasin, Sigal, Samuel, Stanca, Carmen, Steinbook, Michael, Szabo, Gyongyi, Terrault, Norah, Tong, Myron, Victor, David, Zervos, Xaralambos, Harrison, Stephen A., Wong, Vincent Wai-Sun, Caldwell, Stephen H., Shiffman, Mitchell L., Camargo, Marianne, Li, Georgia, Kersey, Kathryn, Jia, Catherine, Zhu, Yanni, Djedjos, C. Stephen, Subramanian, G. Mani, Myers, Robert P., Anstee, Quentin M., Romero-Gomez, Manuel, Goodman, Zachary, Lawitz, Eric J., and Younossi, Zobair

Published
2020
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26. G-CSF increases calprotectin expression, liver damage and neuroinflammation in a murine model of alcohol-induced ACLF.

Author

Ortega-Ribera, Martí, Yuan Zhuang, Brezani, Veronika, Nagesh, Prashanth Thevkar, Joshi, Radhika S., Babuta, Mrigya, Yanbo Wang, and Szabo, Gyongyi

Subjects
CALPROTECTIN, GRANULOCYTE-colony stimulating factor, TYPE I interferons, HEPATIC fibrosis, BILE ducts, LIVER
Abstract

Background and aims: Granulocyte colony-stimulating factor (G-CSF) has been proposed as a therapeutic option for patients with ACLF, however clinical outcomes are controversial. We aimed at dissecting the role of G-CSF in an alcohol-induced murine model of ACLF. Methods: ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis model. A subgroup of mice received two G-CSF (200 μg/kg) or vehicle injections prior to acute decompensation with alcohol. Liver, blood and brain tissues were assessed. Results: Alcohol binge administered to BDL-fibrotic mice resulted in features of ACLF indicated by a significant increase in liver damage and systemic inflammation compared to BDL alone. G-CSF treatment in ACLF mice induced an increase in liver regeneration and neutrophil infiltration in the liver compared to vehicle-treated ACLF mice. Moreover, liver-infiltrating neutrophils in G-CSF-treated mice exhibited an activated phenotype indicated by increased expression of CXC motif chemokine receptor 2, leukotriene B4 receptor 1, and calprotectin. In the liver, G-CSF triggered increased oxidative stress, type I interferon response, extracellular matrix remodeling and inflammasome activation. Circulating IL-1β was also increased after G-CSF treatment. In the cerebellum, G-CSF increased neutrophil infiltration and S100a8/9 expression, induced microglia proliferation and reactive astrocytes, which was accompanied by oxidative stress, and inflammasome activation compared to vehicle treated ACLF mice. Conclusion: In our novel ACLF model triggered by alcohol binge that mimics ACLF pathophysiology, neutrophil infiltration and S100a8/9 expression in the liver and brain indicate increased tissue damage, accompanied by oxidative stress and inflammasome activation after G-CSF treatment. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Protective role of cGAS in NASH is related to the maintenance of intestinal homeostasis.

Author

de Carvalho Ribeiro, Marcelle, Cho, Yeonhee, Mehta, Jeeval, Wang, Xiaojing, Babuta, Mrigya, Copeland, Christopher, Hussein, Hosni, Catalano, Donna, Wang, Yanbo, and Szabo, Gyongyi

Subjects
HEPATIC fibrosis, INTESTINES, HOMEOSTASIS, PROTEIN expression, LABORATORY mice
Abstract

Background & Aims: Various intracellular pathways regulate inflammation in NASH. Cyclic GMP‐AMP synthase (cGAS) is a DNA sensor that activates STING and plays a role in inflammatory diseases. Here, we explored the role of cGAS in hepatic damage, steatosis, inflammation, and liver fibrosis in mouse models of NASH. Methods: cGAS deficient (cGAS‐KO) and STING deficient (STING‐KO) mice received high fat‐high cholesterol‐high sugar diet (HF‐HC‐HSD) or relevant control diets. Livers were evaluated after 16 or 30 weeks. Results: HF‐HC‐HSD diet, both at 16 and 30 weeks, resulted in increased cGAS protein expression as well as in increased ALT, IL‐1β, TNF‐α and MCP‐1 in wild‐type (WT) mice compared to controls. Surprisingly, liver injury, triglyceride accumulation, and inflammasome activation were greater in HF‐HC‐HSD cGAS‐KO compared to WT mice at 16 and to a lesser extent at 30 weeks. STING, a downstream target of cGAS was significantly increased in WT mice after HF‐HC‐HSD. In STING‐KO mice after HF‐HC‐HSD feeding, we found increased ALT and attenuated MCP1 and IL‐1β expression compared to WT mice. Markers of liver fibrosis were increased in cGAS‐ and STING‐KO mice compared to WT on HF‐HC‐HSD. We discovered that cGAS‐KO mice had a significant increase in circulating endotoxin levels on HF‐HC‐HSD that correlated with changes in intestinal morphology which was exacerbated by HF‐HC‐HSD compared to WT mice. Conclusion: Our findings indicate that cGAS or STING deficiency exacerbate liver damage, steatosis, and inflammation in HF‐HC‐HSD diet‐induced NASH, which might be linked to the disruption of the gut barrier. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Alcoholic liver disease

Author

Seitz, Helmut K., Bataller, Ramon, Cortez-Pinto, Helena, Gao, Bin, Gual, Antoni, Lackner, Carolin, Mathurin, Philippe, Mueller, Sebastian, Szabo, Gyongyi, and Tsukamoto, Hidekazu

Published
2018
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38. Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation.

Author

de Carvalho Ribeiro, Marcelle, Iracheta-Vellve, Arvin, Babuta, Mrigya, Calenda, Charles D., Copeland, Christopher, Zhuang, Yuan, Lowe, Patrick P., Hawryluk, Danielle, Catalano, Donna, Cho, Yeonhee, Barton, Bruce, Dasarathy, Srinivasan, McClain, Craig, McCullough, Arthur J., Mitchell, Mack C., Nagy, Laura E., Radaeva, Svetlana, Lien, Egil, Golenbock, Douglas T., and Szabo, Gyongyi

Published
2023
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45. Alcohol's effect on host defense

Author

Szabo, Gyongyi and Saha, Banishree

Subjects
Immunotherapy -- Health aspects, B cells -- Health aspects, Infection -- Health aspects, Virus diseases -- Health aspects, Health
Abstract

Alcohol affects many organs, including the immune system, with even moderate amounts of alcohol influencing immune responses. Although alcohol can alter the actions of all cell populations involved in the [...]

Published
2015

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