Cathelicidin promotes liver repair after acetaminophen-induced liver injury in mice
© 2023 The Author(s)..
Background & Aims: Acetaminophen (APAP)-induced acute liver injury (AILI) is a leading cause of acute liver failure (ALF). N-acetylcysteine (NAC) is only effective within 24 h after APAP intoxication, raising an urgent need for alternative approaches to treat this disease. This study aimed to test whether cathelicidin (Camp), which is a protective factor in chronic liver diseases, protects mice against APAP-induced liver injury and ALF.
Methods: A clinically relevant AILI model and an APAP-induced ALF model were generated in mice. Genetic and pharmacological approaches were used to interfere with the levels of cathelicidin in vivo.
Results: An increase in hepatic pro-CRAMP/CRAMP (the precursor and mature forms of mouse cathelicidin) was observed in APAP-intoxicated mice. Upregulated cathelicidin was derived from liver-infiltrating neutrophils. Compared with wild-type littermates, Camp knockout had no effect on hepatic injury but dampened hepatic repair in AILI and reduced survival in APAP-induced ALF. CRAMP administration reversed impaired liver recovery observed in APAP-challenged Camp knockout mice. Delayed CRAMP, CRAMP(1-39) (the extended form of CRAMP), or LL-37 (the mature form of human cathelicidin) treatment exhibited a therapeutic benefit for AILI. Co-treatment of cathelicidin and NAC in AILI displayed a stronger hepatoprotective effect than NAC alone. A similar additive effect of CRAMP(1-39)/LL-37 and NAC was observed in APAP-induced ALF. The pro-reparative role of cathelicidin in the APAP-damaged liver was attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced neutrophil phagocytosis of necrotic cell debris in an autocrine manner.
Conclusions: Cathelicidin reduces APAP-induced liver injury and ALF in mice by promoting liver recovery via facilitating inflammation resolution, suggesting a therapeutic potential for late-presenting patients with AILI with or without ALF.
Impact and implications: Acetaminophen-induced acute liver injury is a leading cause of acute liver failure. The efficacy of N-acetylcysteine, the only clinically approved drug against acetaminophen-induced acute liver injury, is significantly reduced for late-presenting patients. We found that cathelicidin exhibits a great therapeutic potential in mice with acetaminophen-induced liver injury or acute liver failure, which makes up for the limitation of N-acetylcysteine therapy by specifically promoting liver repair after acetaminophen intoxication. The pro-reparative role of cathelicidin, as a key effector molecule of neutrophils, in the APAP-injured liver is attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced phagocytic function of neutrophils in an autocrine manner.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
JHEP reports : innovation in hepatology - 5(2023), 4 vom: 30. Apr., Seite 100687 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhai, Tingting [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 16.03.2023 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.jhepr.2023.100687 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354287613 |
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| 100 | 1 | |a Zhai, Tingting |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Cathelicidin promotes liver repair after acetaminophen-induced liver injury in mice |
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| 500 | |a Date Revised 16.03.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2023 The Author(s). | ||
| 520 | |a Background & Aims: Acetaminophen (APAP)-induced acute liver injury (AILI) is a leading cause of acute liver failure (ALF). N-acetylcysteine (NAC) is only effective within 24 h after APAP intoxication, raising an urgent need for alternative approaches to treat this disease. This study aimed to test whether cathelicidin (Camp), which is a protective factor in chronic liver diseases, protects mice against APAP-induced liver injury and ALF | ||
| 520 | |a Methods: A clinically relevant AILI model and an APAP-induced ALF model were generated in mice. Genetic and pharmacological approaches were used to interfere with the levels of cathelicidin in vivo | ||
| 520 | |a Results: An increase in hepatic pro-CRAMP/CRAMP (the precursor and mature forms of mouse cathelicidin) was observed in APAP-intoxicated mice. Upregulated cathelicidin was derived from liver-infiltrating neutrophils. Compared with wild-type littermates, Camp knockout had no effect on hepatic injury but dampened hepatic repair in AILI and reduced survival in APAP-induced ALF. CRAMP administration reversed impaired liver recovery observed in APAP-challenged Camp knockout mice. Delayed CRAMP, CRAMP(1-39) (the extended form of CRAMP), or LL-37 (the mature form of human cathelicidin) treatment exhibited a therapeutic benefit for AILI. Co-treatment of cathelicidin and NAC in AILI displayed a stronger hepatoprotective effect than NAC alone. A similar additive effect of CRAMP(1-39)/LL-37 and NAC was observed in APAP-induced ALF. The pro-reparative role of cathelicidin in the APAP-damaged liver was attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced neutrophil phagocytosis of necrotic cell debris in an autocrine manner | ||
| 520 | |a Conclusions: Cathelicidin reduces APAP-induced liver injury and ALF in mice by promoting liver recovery via facilitating inflammation resolution, suggesting a therapeutic potential for late-presenting patients with AILI with or without ALF | ||
| 520 | |a Impact and implications: Acetaminophen-induced acute liver injury is a leading cause of acute liver failure. The efficacy of N-acetylcysteine, the only clinically approved drug against acetaminophen-induced acute liver injury, is significantly reduced for late-presenting patients. We found that cathelicidin exhibits a great therapeutic potential in mice with acetaminophen-induced liver injury or acute liver failure, which makes up for the limitation of N-acetylcysteine therapy by specifically promoting liver repair after acetaminophen intoxication. The pro-reparative role of cathelicidin, as a key effector molecule of neutrophils, in the APAP-injured liver is attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced phagocytic function of neutrophils in an autocrine manner | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a AILI, acetaminophen-induced acute liver injury | |
| 650 | 4 | |a ALF, acute liver failure | |
| 650 | 4 | |a ALT, alanine aminotransferase | |
| 650 | 4 | |a APAP, acetaminophen | |
| 650 | 4 | |a Acetaminophen | |
| 650 | 4 | |a CRAMP, cathelicidin-related antimicrobial peptide | |
| 650 | 4 | |a CYP2E1, cytochrome P450 2E1 | |
| 650 | 4 | |a Cathelicidin | |
| 650 | 4 | |a EGF, endothelial growth factor | |
| 650 | 4 | |a FPR2/ALX, formyl peptide receptor type 2/lipoxin A4 receptor | |
| 650 | 4 | |a GSH, glutathione | |
| 650 | 4 | |a Inflammation resolution | |
| 650 | 4 | |a JNK, c-Jun N-terminal kinase | |
| 650 | 4 | |a KO, knockout | |
| 650 | 4 | |a Liver repair | |
| 650 | 4 | |a Mac-1, macrophage-1 antigen | |
| 650 | 4 | |a NAC, N-acetylcysteine | |
| 650 | 4 | |a NAPQI, N-acetyl-p-benzoquinone imine | |
| 650 | 4 | |a NPC, non-parenchymal cell | |
| 650 | 4 | |a Neutrophils | |
| 650 | 4 | |a Phagocytosis | |
| 650 | 4 | |a ROS, reactive oxygen species | |
| 650 | 4 | |a TLR4, Toll-like receptor 4 | |
| 650 | 4 | |a WT, wild-type | |
| 650 | 4 | |a hCAP18, human cationic antimicrobial protein | |
| 650 | 4 | |a α-SMA, alpha-smooth muscle actin | |
| 700 | 1 | |a Zhang, Jingjing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Bilian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Zhiguang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yan |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:5 |g year:2023 |g number:4 |g day:30 |g month:04 |g pages:100687 |
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