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

• Published in: Clinical science (1979) Vol. 132; no. 2; pp. 255 - 272
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England 31.01.2018
• Subjects: Animals; Carbon Tetrachloride - toxicity; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - metabolism; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Disease Models, Animal; Female; Gene Expression - immunology; Hepatocytes - immunology; Hepatocytes - metabolism; Liver - immunology; Liver - metabolism; Liver Regeneration - immunology; Macrophages - immunology; Macrophages - metabolism; Male; Mice, Inbred BALB C; Monocytes - immunology; Monocytes - metabolism; Sex Factors; Time Factors; Gr-1 monocytes; gender dimorphism; liver inflammatory cells; liver regeneration
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/CS20171260

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 (CCl ) 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 CD11b Gr-1 monocytes expressed AR and were recruited later in male compared with female livers after CCl treatment. Moreover, CD11b AR Gr-1 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 CD11b AR Gr-1 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.