Innate immune cell activation causes lung fibrosis in a humanized model of long COVID

被引：27

作者：

Cui, Lu ^{[1
]}

Fang, Zhuoqing ^{[2
]}

Souza, Cristabelle Madona De ^{[1
]}

Lerbs, Tristan ^{[1
]}

Guan, Yuan ^{[2
]}

Li, Irene ^{[3
,4
]}

Charu, Vivek ^{[1
]}

Chen, Shih-Yu ^{[5
]}

Weissman, Irving ^{[1
,6
]}

Wernig, Gerlinde ^{[1
]}

机构：

[1] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Anesthesiol Pain & Perioperat Med, Sch Med, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Biomed Data Sci, Sch Med, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Radiol, Sch Med, Stanford, CA 94305 USA

[5] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan

[6] Stanford Univ, Ludwig Ctr, Stanford, CA 94305 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 10期

关键词：

long COVID pulmonary fibrosis; innate immunity; immune checkpoint therapy; humanized mouse model; MECHANISMS; PNEUMONIA;

D O I：

10.1073/pnas.2217199120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

COVID-19 remains a global pandemic of an unprecedented magnitude with millions of people now developing "COVID lung fibrosis." Single-cell transcriptomics of lungs of patients with long COVID revealed a unique immune signature demonstrating the upregulation of key proinflammatory and innate immune effector genes CD47, IL-6, and JUN. We modeled the transition to lung fibrosis after COVID and profiled the immune response with single-cell mass cytometry in JUN mice. These studies revealed that COVID mediated chronic immune activation reminiscent to long COVID in humans. It was characterized by increased CD47, IL-6, and phospho-JUN (pJUN) expression which correlated with disease severity and pathogenic fibroblast populations. When we subsequently treated a humanized COVID lung fibrosis model by combined blockade of inflammation and fibrosis, we not only ameliorated fibrosis but also restored innate immune equilibrium indicating possible implications for clinical management of COVID lung fibrosis in patients.

引用

页数：9

共 38 条

[1] Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans [J].

Arunachalam, Prabhu S. ;

Wimmers, Florian ;

Mok, Chris Ka Pun ;

Perera, Ranawaka A. P. M. ;

Scott, Madeleine ;

Hagan, Thomas ;

Sigal, Natalia ;

Feng, Yupeng ;

Bristow, Laurel ;

Tsang, Owen Tak-Yin ;

Wagh, Dhananjay ;

Coller, John ;

Pellegrini, Kathryn L. ;

Kazmin, Dmitri ;

Alaaeddine, Ghina ;

Leung, Wai Shing ;

Chan, Jacky Man Chun ;

Chik, Thomas Shiu Hong ;

Choi, Chris Yau Chung ;

Huerta, Christopher ;

McCullough, Michele Paine ;

Lv, Huibin ;

Anderson, Evan ;

Edupuganti, Srilatha ;

Upadhyay, Amit A. ;

Bosinger, Steve E. ;

Maecker, Holden Terry ;

Khatri, Purvesh ;

Rouphael, Nadine ;

Peiris, Malik ;

Pulendran, Bali .

SCIENCE, 2020, 369 (6508) :1210-+

[2] Lung Fibrosis after COVID-19: Treatment Prospects [J].

Bazdyrev, Evgeny ;

Rusina, Polina ;

Panova, Maria ;

Novikov, Fedor ;

Grishagin, Ivan ;

Nebolsin, Vladimir .

PHARMACEUTICALS, 2021, 14 (08)

[3] Lung transplantation for patients with severe COVID-19 [J].

Bharat, Ankit ;

Querrey, Melissa ;

Markov, Nikolay S. ;

Kim, Samuel ;

Kurihara, Chitaru ;

Garza-Castillon, Rafael ;

Manerikar, Adwaiy ;

Shilatifard, Ali ;

Tomic, Rade ;

Politanska, Yuliya ;

Abdala-Valencia, Hiam ;

Yeldandi, Anjana, V ;

Lomasney, Jon W. ;

Misharin, Alexander, V ;

Budinger, G. R. Scott .

SCIENCE TRANSLATIONAL MEDICINE, 2020, 12 (574)

[4] The COVID-19 immune landscape is dynamically and reversibly correlated with disease severity [J].

Bolouri, Hamid ;

Speake, Cate ;

Skibinski, David ;

Long, S. Alice ;

Hocking, Anne M. ;

Campbell, Daniel J. ;

Hamerman, Jessica A. ;

Malhotra, Uma ;

Buckner, Jane H. .

JOURNAL OF CLINICAL INVESTIGATION, 2021, 131 (03)

[5]

Brown KK, 2020, EUR RESPIR J, V55

[6] Protocol and Reagents for Pseudotyping Lentiviral Particles with SARS-CoV-2 Spike Protein for Neutralization Assays [J].

Crawford, Katharine H. D. ;

Eguia, Rachel ;

Dingens, Adam S. ;

Loes, Andrea N. ;

Malone, Keara D. ;

Wolf, Caitlin R. ;

Chu, Helen Y. ;

Tortorici, M. Alejandra ;

Veesler, David ;

Murphy, Michael ;

Pettie, Deleah ;

King, Neil P. ;

Balazs, Alejandro B. ;

Bloom, Jesse D. .

VIRUSES-BASEL, 2020, 12 (05)

[7] Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity [J].

Cui, Lu ;

Chen, Shih-Yu ;

Lerbs, Tristan ;

Lee, Jin-Wook ;

Domizi, Pablo ;

Gordon, Sydney ;

Kim, Yong-hun ;

Nolan, Garry ;

Betancur, Paola ;

Wernig, Gerlinde .

NATURE COMMUNICATIONS, 2020, 11 (01)

[8]

Del Valle DM, 2020, NAT MED, V26, P1636, DOI [10.1038/s41591-020-1051-9, 10.1101/2020.05.28.20115758]

[9] IL-6 regulates neutrophil trafficking during acute inflammation via STAT3 [J].

Fielding, Ceri A. ;

McLoughlin, Rachel M. ;

McLeod, Louise ;

Colmont, Chantal S. ;

Najdovska, Meri ;

Grail, Dianne ;

Ernst, Matthias ;

Jones, Simon A. ;

Topley, Nicholas ;

Jenkins, Brendan J. .

JOURNAL OF IMMUNOLOGY, 2008, 181 (03) :2189-2195

[10] Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia [J].

Grant, Rogan A. ;

Morales-Nebreda, Luisa ;

Markov, Nikolay S. ;

Swaminathan, Suchitra ;

Querrey, Melissa ;

Guzman, Estefany R. ;

Abbott, Darryl A. ;

Donnelly, Helen K. ;

Donayre, Alvaro ;

Goldberg, Isaac A. ;

Klug, Zasu M. ;

Borkowski, Nicole ;

Lu, Ziyan ;

Kihshen, Hermon ;

Politanska, Yuliya ;

Sichizya, Lango ;

Kang, Mengjia ;

Shilatifard, Ali ;

Qi, Chao ;

Lomasney, Jon W. ;

Argento, A. Christine ;

Kruser, Jacqueline M. ;

Malsin, Elizabeth S. ;

Pickens, Chiagozie O. ;

Smith, Sean B. ;

Walter, James M. ;

Pawlowski, Anna E. ;

Schneider, Daniel ;

Nannapaneni, Prasanth ;

Abdala-Valencia, Hiam ;

Bharat, Ankit ;

Gottardi, Cara J. ;

Budinger, G. R. Scott ;

Misharin, Alexander, V ;

Singer, Benjamin D. ;

Wunderink, Richard G. .

NATURE, 2021, 590 (7847) :635-+

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