Actin-related protein 2/3 complex regulates neutrophil extracellular trap expulsion and lung damage in abdominal sepsis
Ding, Zhiyi LU ; Du, Feifei LU ; Rönnow, Carl Fredrik LU ; Wang, Yongzhi LU ; Rahman, Milladur LU
and Thorlacius, Henrik
LU
(2022)
In American Journal of Physiology - Lung Cellular and Molecular Physiology
322(5).
p.662-672
- Abstract
Neutrophil extracellular trap (NET) formation is a key feature in sepsis. The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2/3 (Arp 2/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil... (More)
Neutrophil extracellular trap (NET) formation is a key feature in sepsis. The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2/3 (Arp 2/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil recruitment, edema formation, and tissue damage in the lungs. Moreover, Arp 2/3 inhibition decreased levels of C-X-C motif chemokine ligand 1 (CXCL-1) and interleukin-6 in the lung and plasma of septic animals. Taken together, this study shows that expulsion of NETs is regulated by the actin cytoskeleton and that inhibition of Arp 2/3-dependent F-actin polymerization not only decreases NET formation but also protects against pathological inflammation and tissue damage in septic lung injury. Thus, we suggest that targeting NET release is a novel and useful way to ameliorate lung damage in abdominal sepsis.
(Less)
- author
- Ding, Zhiyi
LU
; Du, Feifei
LU
; Rönnow, Carl Fredrik
LU
; Wang, Yongzhi
LU
; Rahman, Milladur
LU
and Thorlacius, Henrik
LU
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- cytoskeleton, infection, inflammation, leukocyte, sepsis, tissue injury
- in
- American Journal of Physiology - Lung Cellular and Molecular Physiology
- volume
- 322
- issue
- 5
- pages
- 662 - 672
- publisher
- American Physiological Society
- external identifiers
-
- scopus:85128799914
- pmid:35272488
- ISSN
- 1040-0605
- DOI
- 10.1152/AJPLUNG.00318.2021
- language
- English
- LU publication?
- yes
- id
- 4911ea61-7cd0-4342-b1ad-5cb85783ef5d
- date added to LUP
- 2022-07-01 13:50:16
- date last changed
- 2024-04-18 12:44:08
@article{4911ea61-7cd0-4342-b1ad-5cb85783ef5d,
abstract = {{<p>Neutrophil extracellular trap (NET) formation is a key feature in sepsis. The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2/3 (Arp 2/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil recruitment, edema formation, and tissue damage in the lungs. Moreover, Arp 2/3 inhibition decreased levels of C-X-C motif chemokine ligand 1 (CXCL-1) and interleukin-6 in the lung and plasma of septic animals. Taken together, this study shows that expulsion of NETs is regulated by the actin cytoskeleton and that inhibition of Arp 2/3-dependent F-actin polymerization not only decreases NET formation but also protects against pathological inflammation and tissue damage in septic lung injury. Thus, we suggest that targeting NET release is a novel and useful way to ameliorate lung damage in abdominal sepsis.</p>}},
author = {{Ding, Zhiyi and Du, Feifei and Rönnow, Carl Fredrik and Wang, Yongzhi and Rahman, Milladur and Thorlacius, Henrik}},
issn = {{1040-0605}},
keywords = {{cytoskeleton; infection; inflammation; leukocyte; sepsis; tissue injury}},
language = {{eng}},
number = {{5}},
pages = {{662--672}},
publisher = {{American Physiological Society}},
series = {{American Journal of Physiology - Lung Cellular and Molecular Physiology}},
title = {{Actin-related protein 2/3 complex regulates neutrophil extracellular trap expulsion and lung damage in abdominal sepsis}},
url = {{http://dx.doi.org/10.1152/AJPLUNG.00318.2021}},
doi = {{10.1152/AJPLUNG.00318.2021}},
volume = {{322}},
year = {{2022}},
}