Inflammatory arthritis increases the susceptibility to acute immune-mediated hepatitis in mice through enhancing leptin expression in T cells
Graphical abstract
Introduction
The liver is amongst the largest solid organ in the body. It has various immunological properties, such as the induction of complement components, acute phase proteins, cytokines, and chemokines, as well as the existence of diverse populations of resident immune cell populations (Robinson et al., 2016). Notably, the liver plays a crucial function in sensing and resolving systemic inflammation. There is ample evidence that excessive or dysregulated inflammatory response in the liver might cause autoimmune, infectious, and chronic inflammatory diseases. Importantly, inflammation generated by liver-resident immune cells and non-hematopoietic cells plays a vital role in maintaining liver and systemic homeostasis (Bieghs and Trautwein, 2013; Robinson et al., 2016). In contrast, liver inflammation often occurs when hepatocytes are attacked by a disease-causing microorganism or agent (Talwani et al., 2011). Subsequently, the inflammation breaks down the immune tolerance in the liver, resulting in further local hepatic inflammatory responses. A critical interplay within the liver and the primary organ initiates the immune and inflammatory response (Radovanovic-Dinic et al., 2018; Uko et al., 2012). The interplay is particularly important in the case of autoimmune and chronic liver diseases, in which the host immune response is often relatively ineffective.
Inflammatory arthritis is an autoimmune disorder that an over-reactive immune response attacks joint tissues, which includes rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), and other seronegative spondyloarthritis (Fang et al., 2020). Interestingly, abnormal liver function tests are commonly observed in patients with inflammatory arthritis (Fernandes et al., 1979; Hiejima et al., 2012; Pakchotanon et al., 2020; Selmi et al., 2011; Wolfe, 1997). The gamma-glutamyl transferase (GGT) test is used to help detect liver disorders and bile duct problems (Koenig and Seneff, 2015). It has been reported that the serum level of GGT was increased in 23 % of the RA patients (Fernandes et al., 1979). It is worth mentioning that the level of GGT has a significant correlation with the serum level of erythrocyte sedimentation rate (ESR), a necessary clinical marker for evaluating disease activity in patients with RA (Wolfe, 1997). Abnormal liver biopsies were reported in 65 % of unselected patients with RA, with mild portal chronic inflammatory infiltration, small foci of necrosis, and fatty liver (Selmi et al., 2011). Pakchotanon et al., conducted a longitudinal cohort study recruiting a large number of PsA patients and noted that the risk for liver disease was higher among PsA patients than psoriasis alone (Pakchotanon et al., 2020). Additionally, acute liver failure is an infrequent complication in patients with systemic JIA (Hiejima et al., 2012). Although the coexistence of liver dysfunction and inflammatory arthritis was widely reported in clinical studies, the potential mechanism is rarely investigated.
It is well-known that the primary immune disease of the liver is autoimmune hepatitis (AIH), which has characteristic features of autoimmunity. Aberrant T cell responses play a significant role in the immunopathogenesis of AIH (Mizuhara et al., 1994; Tiegs et al., 1992b). Con A-induced hepatitis is a well-established experimental model that Tiegs et al., have established since 1992. Intravenous injection of Con A activates hepatic T cells to secrete inflammatory cytokines, which cause multiple hepatocyte necrosis and serum alanine transaminase (ALT) elevation in mice. Therefore, this model could simulate the clinical and histological symptoms of human autoimmune hepatitis and have been used to elucidate the underlying mechanisms of T cell-mediated autoimmune hepatitis (Tiegs et al., 1992b).
In this study, we generated the mice with inflammatory arthritis using the adjuvant-induced arthritis (AIA) model, which is a very reproducible model of chronic immune-mediated joint inflammation (Dong et al., 2019). The results show that arthritis mice got severe hepatitis compared with control mice after Con A administration. We found that the hepatic T cells from AIA mice produced a higher level of leptin, an adipokine that can modulate the survival and activity of immune cells (Francisco et al., 2018). Moreover, we provided evidence that increased leptin expression is responsible for the hypersensitivity of T cells in arthritis mice. In summary, our findings revealed an essential role of leptin in the connection between inflammatory arthritis and AIH, which provides a better understanding of arthritis-related liver disorders.
Section snippets
Mice
Wild-type C57BL/6 mice were purchased from the Laboratory Animal Center of Southern Medical University (Guangzhou, China). The mice were housed under a specific pathogen-free condition, on a 12 -h light-dark cycle, and with food and water ad libitum. All animal experiments in this study were approved by the Welfare and Ethical Committee for Experimental Animal Care of Southern Medical University.
Reagents
Con A was purchased from Sigma-Aldrich (St. Louis, MO, USA). Anti-phospho-STAT1 antibody (58D6),
Arthritis mice are highly susceptible to Con A-induced hepatitis
To assess the pathogenic relationship of inflammatory arthritis and immune-mediated hepatitis, control and arthritis mice received an intravenous injection of Con A at the dose of 7.5 mg/kg body weight. Histological analysis demonstrated that Con A-treated arthritis mice got severe liver necrosis compared with their control counterparts. The necrotic area of livers from arthritis mice was much higher than that from control mice after Con A injection (Fig. 1A). Besides, TUNEL positive cells were
Discussion
In the present study, we have demonstrated a relationship between inflammatory arthritis and immune-mediated hepatitis by administering Con A to the AIA model mice. Our studies revealed that liver injury was worse in arthritis/Con A-treated mice compared to other mice. Moreover, hepatic T cells from arthritis mice were more sensitive to Con A stimulation than those from control mice. Furthermore, we also provided in vitro evidence indicating that T cell-producing leptin might be responsible for
Author statement
Youyi Wang: Methodology, Validation, Formal analysis, Investigation, Writing–original draft. Ping Wang: Methodology, Formal analysis, Investigation. Qishan Xu: Methodology, Formal analysis, Investigation. Lijun Dong: Methodology, Investigation. Yunzhi Liu: Methodology, Software, Visualization. Yu Chen: Methodology, Investigation. Jia Zhou: Conceptualization, Resources. Xiao Lu: Software, Formal analysis. Daming Zuo: Conceptualization, Methodology, Supervision, Resources, Funding acquisition,
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
This work was supported in part by the National Natural Science Foundation of China (grant nos.: 82173083, 82071781, and 81802410), Science and Technology Planning Project of Guangzhou (grant no.: 202002030160), Innovation team of chronic kidney disease with integrated traditional Chinese and Western Medicine (grant no.: 2019KCXTD014).
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