Role of hepatic resident and infiltrating macrophages in liver repair after acute injury☆
Graphical abstract
Introduction
Liver disease is a significant health problem, affecting millions of people in the world. Currently, transplantation is the only effective treatment for acute liver failure and end-stage chronic liver injury. However, transplantation is costly, challenging, and well-matched donor tissues are not readily available. Therefore, there is a pressing need to develop pharmacological treatments. One area of research that holds promise of breakthrough discoveries is better understanding of the liver's own repair and regeneration processes. The majority of studies of liver regeneration have used animal models of partial hepatectomy. However, hepatectomy often lacks the cell death and tissue inflammation that are commonly observed in acute and chronic liver injury. Therefore, the present study aimed to investigate liver repair processes after overdose of acetaminophen (APAP)-induced liver injury (AILI), which itself is a significant clinical problem [1]. Macrophages/monocytes play important roles in liver injury and liver repair. They produce pro- and anti-inflammatory mediators which can trigger hepatocytic cell death pathways as well as activate protective signaling pathways [2], [3]. Damage-associated molecular pattern molecules (DAMPS), such as high-mobility group box 1 protein and heat shock proteins [4] [5], are released during liver injury and activate macrophages to produce cytokines and chemokines. Macrophage-derived soluble mediators can exacerbate cellular injury or inhibit cell death and promote hepatocyte proliferation [2]. Another important function of macrophages is to phagocytose dead cells and cellular debris [6], [7], [8]. As result, these cells produce angiogenic factors and growth factors, thereby promoting tissue repair.
There are at least two types of macrophages in the liver after acute injury, resident macrophages (Kupffer cells, KCs) and infiltrating macrophages. We have reported that APAP challenge causes hepatic recruitment of circulating monocytes in C–C chemokine receptor type 2 (CCR2)-dependent manner [9]. Our studies also demonstrated that the lack of infiltrating macrophages (IMs) in CCR2−/− mice resulted in a slight delay in tissue recovery from APAP-induced liver injury (AILI). However, the observation that liver repair was completed by 72 h in CCR2−/− mice (versus 48 h in WT mice) suggested that resident Kupffer cells are also involved in liver repair and can compensate for the lack of IMs. Hence, the present study aims to investigate the combined role of resident and infiltrating hepatic Macs during tissue repair.
We developed a mouse model in which either or both populations of hepatic Macs (resident KCs and IMs) could be depleted. We found that the liver repaired and histology returned to normal by day 3 after APAP in mice with intact hepatic Macs or lack of either population of Macs; however, necrotic areas remained prominent in mice with the combined absence of both populations of Macs. Moreover, our data revealed an important angiogenic function of hepatic Macs that plays an integral role in liver repair from AILI.
Section snippets
Animal treatment and assessment of hepatotoxicity
Seven–ten week old male BALB/cJ wild-type (WT, Jackson Laboratories, Bar Harbor, ME) and CCR2−/− mice [on Balb/cJ background, provided by Cara L. Mack, M.D. (Department of Pediatrics, School of Medicine, University of Colorado Denver)] were used. All animal procedures were approved by the Institutional Animal Care and Use Committee of the University of Colorado Anschutz Medical Campus. Animals were fasted overnight for approximately 16 h to deplete glutathione levels, prior to intraperitoneal
The combined absence of KCs and IMs markedly delays liver repair after AILI
In the present study we developed an in vivo approach to assess the roles of KCs and IMs in the progression and regression of AILI by using 4 groups of mice having none, either, or both populations of the hepatic Macs (see Section 2).
At 24 h after APAP treatment, the ALT levels (Fig. 1B) were similar and liver histopathology (Fig. 1A, 24 h) was comparable across the 4 groups. These data suggested that the extent of initial hepatic injury was not impacted by the absence of either or both
Discussion
Liver disease caused by various etiologies, such as viral infection, alcohol or drug ingestion, metabolic disorders, and autoimmunity affect approximately 150,000 new patients in the U.S. each year [18]. Although liver transplantation is an effective treatment for chronic and acute liver failure, the limited options for therapeutic interventions remain a pressing issue of treating liver disease. A better understanding the liver's own repair and regeneration processes may lead to discoveries of
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2022, International ImmunopharmacologyCitation Excerpt :Accumulated evidences suggest that macrophages contribute to the pathogenesis of AILI [2]. In the mouse AILI model, pro-inflammatory macrophages are recruited to necrotic areas and highly express Ly6C, TNF-α,IL-1β and IL-6, which may be a key event during the early period of AILI [3–6]. It was reported that the pharmacological activation of Gpbar1 improved AILI through inhibiting macrophage recruitment and inducing the phenotype transformation of macrophages [7].
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Financial support: U.S. National Institutes of Health grant RO1 ES012914 (to C.J.) and The ALSAM Foundation Skaggs Scholars Program Award (to C.J.).