Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury

Debora Bizzaro, Marika Crescenzi, Rosa Di Liddo, Diletta Arcidiacono, Andrea Cappon, Thomas Bertalot, Vincenzo Amodio, Alessia Tasso, Annalisa Stefani, Valentina Bertazzo, Giacomo Germani, Chiara Frasson, Giuseppe Basso, Pierpaolo Parnigotto, Malcolm Ronald Alison, Patrizia Burra, Maria Teresa Conconi, Francesco Paolo Russo

Research output: Contribution to journalArticle

Abstract

A sexual dimorphism in liver inflammation and repair was previously demonstrated. Its cellular dissection in the course of acute liver injury (ALI) was explored. BALB/c mice were treated with carbon tetrachloride (CCl4) by intraperitoneal injection and killed after 3, 5, and 8 days. Histological and hepatic cell population analyses were performed. The correlation between androgen receptor (AR) expression and liver recruited inflammatory cells was investigated by treatment with the AR antagonist flutamide. Additionally, patients with a diagnosis of drug induced liver injury (DILI) were included in the study, with a particular focus on gender dimorphism in circulating monocytes. A delayed resolution of necrotic damage and a higher expression of proinflammatory cytokines were apparent in male mice along with a slower recruitment of inflammatory monocytes. F4/80+CD11b+ macrophages and CD11bhighGr-1high monocytes expressed AR and were recruited later in male compared with female livers after CCl4 treatment. Moreover, CD11bhighAR+Gr-1high recruitment was negatively modulated by flutamide in males. Analysis of DILI patients showed overall a significant reduction in circulating mature monocytes compared with healthy subjects. More interestingly, male patients had higher numbers of immature monocytes compared with female patients.A stronger cytotoxic tissue response was correlated with an impaired recruitment of CD11bhighAR+Gr-1high cells and F4/80+CD11b+ macrophages in the early inflammatory phase under AR signaling. During DILI, a dimorphic immune response was apparent, characterized by a massive recruitment of monocytes to the liver both in males and females, but only in males was this recruitment sustained by a turnover of immature monocytes.

Original languageEnglish
Pages (from-to)255-272
Number of pages18
JournalClinical Science
Volume132
Issue number2
DOIs
Publication statusPublished - Jan 31 2018

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Liver Regeneration
Sex Characteristics
Monocytes
Liver
Chemical and Drug Induced Liver Injury
Wounds and Injuries
Androgen Receptors
Flutamide
Androgen Receptor Antagonists
Macrophages
Carbon Tetrachloride
Intraperitoneal Injections
Dissection
Hepatocytes
Healthy Volunteers
Cytokines
Inflammation
Therapeutics
Population

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Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury. / Bizzaro, Debora; Crescenzi, Marika; Di Liddo, Rosa; Arcidiacono, Diletta; Cappon, Andrea; Bertalot, Thomas; Amodio, Vincenzo; Tasso, Alessia; Stefani, Annalisa; Bertazzo, Valentina; Germani, Giacomo; Frasson, Chiara; Basso, Giuseppe; Parnigotto, Pierpaolo; Alison, Malcolm Ronald; Burra, Patrizia; Conconi, Maria Teresa; Russo, Francesco Paolo.

In: Clinical Science, Vol. 132, No. 2, 31.01.2018, p. 255-272.

Research output: Contribution to journalArticle

Bizzaro, D, Crescenzi, M, Di Liddo, R, Arcidiacono, D, Cappon, A, Bertalot, T, Amodio, V, Tasso, A, Stefani, A, Bertazzo, V, Germani, G, Frasson, C, Basso, G, Parnigotto, P, Alison, MR, Burra, P, Conconi, MT & Russo, FP 2018, 'Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury', Clinical Science, vol. 132, no. 2, pp. 255-272. https://doi.org/10.1042/CS20171260
Bizzaro, Debora ; Crescenzi, Marika ; Di Liddo, Rosa ; Arcidiacono, Diletta ; Cappon, Andrea ; Bertalot, Thomas ; Amodio, Vincenzo ; Tasso, Alessia ; Stefani, Annalisa ; Bertazzo, Valentina ; Germani, Giacomo ; Frasson, Chiara ; Basso, Giuseppe ; Parnigotto, Pierpaolo ; Alison, Malcolm Ronald ; Burra, Patrizia ; Conconi, Maria Teresa ; Russo, Francesco Paolo. / Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury. In: Clinical Science. 2018 ; Vol. 132, No. 2. pp. 255-272.
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abstract = "A sexual dimorphism in liver inflammation and repair was previously demonstrated. Its cellular dissection in the course of acute liver injury (ALI) was explored. BALB/c mice were treated with carbon tetrachloride (CCl4) by intraperitoneal injection and killed after 3, 5, and 8 days. Histological and hepatic cell population analyses were performed. The correlation between androgen receptor (AR) expression and liver recruited inflammatory cells was investigated by treatment with the AR antagonist flutamide. Additionally, patients with a diagnosis of drug induced liver injury (DILI) were included in the study, with a particular focus on gender dimorphism in circulating monocytes. A delayed resolution of necrotic damage and a higher expression of proinflammatory cytokines were apparent in male mice along with a slower recruitment of inflammatory monocytes. F4/80+CD11b+ macrophages and CD11bhighGr-1high monocytes expressed AR and were recruited later in male compared with female livers after CCl4 treatment. Moreover, CD11bhighAR+Gr-1high recruitment was negatively modulated by flutamide in males. Analysis of DILI patients showed overall a significant reduction in circulating mature monocytes compared with healthy subjects. More interestingly, male patients had higher numbers of immature monocytes compared with female patients.A stronger cytotoxic tissue response was correlated with an impaired recruitment of CD11bhighAR+Gr-1high cells and F4/80+CD11b+ macrophages in the early inflammatory phase under AR signaling. During DILI, a dimorphic immune response was apparent, characterized by a massive recruitment of monocytes to the liver both in males and females, but only in males was this recruitment sustained by a turnover of immature monocytes.",
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T1 - Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury

AU - Bizzaro, Debora

AU - Crescenzi, Marika

AU - Di Liddo, Rosa

AU - Arcidiacono, Diletta

AU - Cappon, Andrea

AU - Bertalot, Thomas

AU - Amodio, Vincenzo

AU - Tasso, Alessia

AU - Stefani, Annalisa

AU - Bertazzo, Valentina

AU - Germani, Giacomo

AU - Frasson, Chiara

AU - Basso, Giuseppe

AU - Parnigotto, Pierpaolo

AU - Alison, Malcolm Ronald

AU - Burra, Patrizia

AU - Conconi, Maria Teresa

AU - Russo, Francesco Paolo

N1 - © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

PY - 2018/1/31

Y1 - 2018/1/31

N2 - A sexual dimorphism in liver inflammation and repair was previously demonstrated. Its cellular dissection in the course of acute liver injury (ALI) was explored. BALB/c mice were treated with carbon tetrachloride (CCl4) by intraperitoneal injection and killed after 3, 5, and 8 days. Histological and hepatic cell population analyses were performed. The correlation between androgen receptor (AR) expression and liver recruited inflammatory cells was investigated by treatment with the AR antagonist flutamide. Additionally, patients with a diagnosis of drug induced liver injury (DILI) were included in the study, with a particular focus on gender dimorphism in circulating monocytes. A delayed resolution of necrotic damage and a higher expression of proinflammatory cytokines were apparent in male mice along with a slower recruitment of inflammatory monocytes. F4/80+CD11b+ macrophages and CD11bhighGr-1high monocytes expressed AR and were recruited later in male compared with female livers after CCl4 treatment. Moreover, CD11bhighAR+Gr-1high recruitment was negatively modulated by flutamide in males. Analysis of DILI patients showed overall a significant reduction in circulating mature monocytes compared with healthy subjects. More interestingly, male patients had higher numbers of immature monocytes compared with female patients.A stronger cytotoxic tissue response was correlated with an impaired recruitment of CD11bhighAR+Gr-1high cells and F4/80+CD11b+ macrophages in the early inflammatory phase under AR signaling. During DILI, a dimorphic immune response was apparent, characterized by a massive recruitment of monocytes to the liver both in males and females, but only in males was this recruitment sustained by a turnover of immature monocytes.

AB - A sexual dimorphism in liver inflammation and repair was previously demonstrated. Its cellular dissection in the course of acute liver injury (ALI) was explored. BALB/c mice were treated with carbon tetrachloride (CCl4) by intraperitoneal injection and killed after 3, 5, and 8 days. Histological and hepatic cell population analyses were performed. The correlation between androgen receptor (AR) expression and liver recruited inflammatory cells was investigated by treatment with the AR antagonist flutamide. Additionally, patients with a diagnosis of drug induced liver injury (DILI) were included in the study, with a particular focus on gender dimorphism in circulating monocytes. A delayed resolution of necrotic damage and a higher expression of proinflammatory cytokines were apparent in male mice along with a slower recruitment of inflammatory monocytes. F4/80+CD11b+ macrophages and CD11bhighGr-1high monocytes expressed AR and were recruited later in male compared with female livers after CCl4 treatment. Moreover, CD11bhighAR+Gr-1high recruitment was negatively modulated by flutamide in males. Analysis of DILI patients showed overall a significant reduction in circulating mature monocytes compared with healthy subjects. More interestingly, male patients had higher numbers of immature monocytes compared with female patients.A stronger cytotoxic tissue response was correlated with an impaired recruitment of CD11bhighAR+Gr-1high cells and F4/80+CD11b+ macrophages in the early inflammatory phase under AR signaling. During DILI, a dimorphic immune response was apparent, characterized by a massive recruitment of monocytes to the liver both in males and females, but only in males was this recruitment sustained by a turnover of immature monocytes.

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VL - 132

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JF - Clinical Science

SN - 0143-5221

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