It is well known that HBV is a partially double-stranded DNA virus that affects 350 million individuals worldwide (16). After HBV enters the body, it replicates and assembles in liver cells, and activates the immune response by altering the liver metabolic function or producing a variety of viral proteins, thus resulting in liver damage (18). Accumulating data have indicated that multiple key molecules and proteins participate in HBV-induced liver injury at different levels, including miR-155. Although liver cells are not immune cells, they can express innate immune receptors. Sarkar et al (19) reported that miR-155 was downregulated in HBV-infected liver biopsy and serum samples, as well as in HepG2.2.15 cells (HBV stably replicated liver cancer cell line), and that the expression of toll-like receptor (TLR)7 was positively correlated with that of miR-155. The suggested underlying mechanism was that TLR7 induced the expression of miR-155 through NF-κB signaling, and the upregulation of miR-155 could reduce HBV load by targeting CCAAT/enhancer-binding protein-β (C/EBP-β) in HCC cells (19). Furthermore, Su et al (20) demonstrated that the ectopic overexpression of miR-155 promoted activation of the JAK/STAT signaling pathway by targeting SOCS1, and markedly inhibited HBV replication by increasing innate antiviral immunity, including the production of type I interferon (IFN) and the expression of IFN-inducible antiviral genes in hepatocytes. However, another study indicated that miR-155 was increased in HCC cells, and stimulated autophagy by downregulating SOCS1, enhancing Akt phosphorylation and inhibiting mechanistic target of rapamycin (mTOR) phosphorylation through the SOCS1/Akt/mTOR axis, thereby enhancing HBV replication in HCC cells (21). In addition, our previous study indicated that hepatitis B e antigen induced the expression of macrophage miR-155 through the PI3K and NF-κB signaling pathways, and increased the expression and secretion of inflammatory cytokines in macrophages by targeting Bcl-6, SHIP-1 and SOCS-1 to promote liver injury (22). Therefore, miR-155-mediated HBV replication remains controversial, and more research is required to further determine the role of miR-155 in this process. However, these findings suggested that miR-155 may participate in liver injury by regulating the macrophage-mediated immune response.

Unlike HBV, HCV is a single-stranded hepatotropic RNA virus and the leading cause of chronic hepatitis and liver disease in the world (23,24). HCV-infected hepatocytes lead to liver damage through virus self-replication and the immune response (23). Growing evidence has indicated that miR-155 may affect the replication and life cycle of HCV, and could be employed by host cells and the virus to control or accelerate viral infection. Kałużna (25) showed that miR-155 had an abnormally high expression in HCV-infected patients and induced an inflammatory response. Moreover, even after the completion of antiviral therapy, miR-155 promoted the replication and persistence of the virus. miR-155 was also shown to be related to the inhibition of apoptosis and increased proliferation of hepatocytes, which facilitated the growth of liver cancer (25). Zhang et al (10) reported that the levels of the transcriptional co-activator, P300, were increased in HCV-infected hepatocytes, which activated the NF-κB pathway, resulting in aggravated liver damage and enhanced expression of miR-155. In addition, upregulation of miR-155 activated the Wnt/β-catenin signaling pathway by targeting adenomatous polyposis coli (APC), thereby promoting the proliferation of hepatocytes and tumorigenesis (10). In addition, Grek et al (26) revealed that the replication of HCV RNA was accompanied by an obvious increase in miR-155 expression. The appearance of the negative strand of the virus RNA was closely associated with a higher level of BIC RNA and Dicer protein in peripheral blood mononuclear cells of patients with chronic HCV (CHC) (26). Jiang et al (27) demonstrated that the levels of miR-155 were significantly increased in the liver of HCV-infected patients and were negatively correlated with viral load; however, miR-155 was not correlated with inflammatory grade, fibrosis stage and HCV genotype. In addition, it was demonstrated that the expression of miR-155 was closely associated with the expression of hepatic genes, such as TGF-β, IL-10, TLR3, IFN-stimulated gene 15 and IFN-induced protein with tetratricopeptide repeats 1. Mechanistically, this previous study demonstrated that NF-κB-controlled miR-155 abrogated the immunosuppressive effects of TGF-β and IL-10 on TLR3-mediated antiviral activity in murine Kupffer cells (KCs) and sinusoidal endothelial cells to promote liver injury (27). Furthermore, it has been shown that TLR4 and TLR8 ligands, as well as non-structural (NS)3, NS5 and HCV core proteins, can induce miR-155 expression and TNF-α production in human monocytes. A statistically significant increase in the serum levels of miR-155 was observed in patients with chronic HCV infection compared with those in the normal controls, which may be an indicator of inflammation-caused liver damage (24). Cheng et al (28) verified that the expression levels of T-cell immunoglobulin mucin-3 (Tim-3) and T-box expressed in T cells (T-bet) were upregulated, whereas those of miR-155 were downregulated in NK cells following HCV infection. The reconstitution of miR-155 by transfecting its mimics resulted in a decrease in Tim-3 and T-bet expression and an increase in the levels of IFN-γ in NK cells by promoting the phosphorylation of STAT5 (28). These findings suggested that miR-155 may not only affect virus replication by regulating the function of liver parenchymal or non-parenchymal cells, but may also enhance immune cell function to cause liver damage or accelerate the proliferation of hepatocytes and inhibit their apoptosis, thereby initiating the occurrence of liver cancer.

Excessive drinking over a long period of time can lead to inflammation in several organs, including the liver and brain (31). A previous study demonstrated that alcohol consumption induced miR-155 expression in mice, and miR-155 deficiency protected mice from alcohol-mediated inflammation by inhibiting an increase in the cytokines, monocyte chemoattractant protein-1 (MCP-1) and TNF-α (31). Long-term and chronic drinking have been shown to increase the sensitization of KCs to gut-derived LPS stimulation and lead to more severe inflammatory responses in the liver (29). Given the potential effect of miRNAs on LPS-induced macrophage activation, Bala et al (32,33) demonstrated that chronic alcohol treatment induced a time-dependent increase in the levels of miR-155 in macrophages in vivo and in vitro, which was linearly correlated with TNF-α production. Furthermore, alcohol pretreatment enhanced the LPS-induced expression of macrophage miR-155. Mechanistically, it was indicated that activation of the NF-κB signaling pathway upregulated miR-155 expression, which contributed to alcohol-induced TNF-α production by enhancing the stability of its mRNA via the human antigen R protein (32,33). In addition, based on the increased miR-155 expression in the hepatocytes of alcohol-fed mice compared with pair-fed mice, Bala and Szabo (33) revealed that overexpression of miR-155 in mouse primary hepatocytes led to a decrease in SOCS1 and C/EBP-β proteins, which participate in alcoholic liver disease (ALD) as tumor suppressors and mediators of oxidative stress (33). In addition, Babuta et al (34) identified an autophagic and exosomal function disorder in ALD and alcoholic hepatitis by detecting p62 and LC3-II levels. Secondly, it was demonstrated that alcohol-induced miR-155 could target and inhibit mTOR, Ras homolog enriched in brain (Rheb), lysosomal-associated membrane protein (LAMP)1 and LAMP2 activity of macrophages and hepatocytes to impair autophagic flux, thereby facilitating exosome release and inducing autophagy to remove pathogenic or damaged proteins and nucleic acids to accelerate liver injury (34). Therefore, miR-155 may affect alcohol-induced liver injury mainly through cellular oxidative stress, inflammatory cytokine production, exosome biosynthesis and autophagy.

DILI is a disease that occurs mainly in individuals who have been exposed to certain drugs, herbs or dietary supplements; DILI poses a serious threat to patient health and is an important issue that needs to be taken into consideration during drug development (30). The mechanism underlying DILI is primarily immune-mediated and is often associated with genetic risk determined by human leukocyte antigen variation (35). In severe cases, it may lead to hospitalization, and even liver failure, liver transplantation or death. DILI often shares symptoms with a variety of acute and chronic diseases, including hepatitis, cholestasis, steatosis and fibrosis (36). From a mechanistic point of view, it mainly includes the failure of drug metabolic pathways, cell death, the recruitment and activation of inflammatory leukocytes, such as monocytes and lymphocytes, and the activation of local immune cells, such as KCs (37). miR-155 has been reported to participate in the occurrence and development of DILI through the aforementioned mechanisms. For example, Yuan et al (38) reported that the levels of miR-155 were markedly enhanced in the liver and blood following the administration of acetaminophen. Conversely, miR-155 knockout activated NF-κB by enhancing p65 signaling and abnormal expression of IκB kinase (a direct target of miR-155), which increased serum aspartate aminotransferase and alanine aminotransferase (ALT) levels, and significantly increased the levels of various inflammatory mediators, such as TNF-α and IL-6, leading to a further deterioration of liver injury (38). Therefore, it was hypothesized that the significantly upregulated miR-155 following acetaminophen treatment may protect individuals from acetaminophen-induced liver damage. In addition, anti-tuberculosis (TB) drugs have been shown to induce liver injury, which constitutes a serious side effect of TB therapy and may negatively affect patient compliance (39). Isoniazid (INH) is a first-line medication for TB; however, hepatotoxicity is a frequent adverse effect of INH that may promote the progression of liver cirrhosis (40). Song et al (41) demonstrated that the expression of miR-155, participating in endotoxin shock caused by lipopolysaccharide/TNF-α (42), was increased in mice treated with INH, which in turn enhanced the expression of TNF-α by regulating the Fas-associated death domain and exacerbated liver damage by increasing the inflammatory response. Furthermore, Wan et al (43) revealed that the synthetic chemical compound perfluorooctanesulfonic acid (PFOS) resulted in hepatotoxicity after accumulating in the liver, and significantly upregulated miR-155 expression by activating reactive oxygen species in liver cells. The inhibition of miR-155 further reduced cytotoxicity and oxidative stress in hepatocytes exposed to PFOS exposure by targeting the NF-E2-related factor 2 (Nrf2) signaling pathway to prevent oxidative liver damage (43). These findings indicated that miR-155 may target multiple genes, and play an essential role in DILI through cellular inflammatory responses and oxidative stress.

AIH is a chronic, progressive autoimmune disease characterized by liver inflammation, elevated transaminase levels and the activation of intrahepatic lymphocytes (61,62). A previous study reported that the expression levels of miR-155 were increased in peripheral blood monocytes and liver tissues from patients with AIH. The dominant mechanism is that miR-155 can regulate the differentiation and recruitment of Th17/regulatory T (Treg) cells by targeting SOCS1 and SHIP1. Inhibition of miR-155 may inhibit Th17-mediated expression and secretion of pro-inflammatory IL-10, but not Treg-mediated production of anti-inflammatory IL-10, thus suggesting that miR-155 may accelerate liver damage (61). Thus, miR-155 may be a regulator of AIH affected by adaptive immunity, and miR-155 antagonists may be used to inhibit the occurrence of AIH to a certain extent.

During sepsis, the liver is particularly vulnerable to damage (63). Severe sepsis-induced liver injury may subsequently lead to multiple organ dysfunction syndrome (64). It has been reported that miR-155, upregulated in septic liver injury, may serve a pivotal role (65,66). Yang et al (65) reported that antagomiR-155 relieved LPS-induced septic liver injury, as determined by the improved body weight and survival rate of mice, by restraining the infiltration of inflammatory cells and necrosis of liver cells, and suppressing ALT levels (65). Mechanistically, this previous study revealed that antagomiR-155 alleviated liver injury through controlling mitochondrial dysfunction, oxidative stress-mediated ER stress and hepatocyte apoptosis by targeting Nrf2, and enhancing SOCS1 expression and deactivating JAK/STAT signaling (65,66). Furthermore, Li et al (67) demonstrated that, following exposure to LPS, the expression levels of MCP-1-induced protein-1 in macrophages were significantly upregulated, leading to a marked downregulation of miR-155 expression. This resulted in the upregulation of RAR-related orphan receptor α, which reduced the inflammatory response by regulating NF-κB signaling, and thus alleviated the symptoms of septic liver injury (67). These results suggested that miR-155 may serve as a therapeutic target in septic liver injury.

According to the speed of disease development, liver failure can be divided into acute, subacute, chronic plus acute, and chronic liver failure. Liver failure generally refers to ALF. During ALF, circulating proinflammatory cytokines, including IL-6, TNF-α, IL-1-β, IL-12, IL-10 and IFN-γ, are regulated by immune cascade activation following LPS binding to TLR4 (68). This leads to marked hepatocyte apoptosis/necrosis due to an excessive immune response, which is severely life threatening (69). Zhang et al (70) demonstrated that hepatic miR-155 expression is increased at all time points in the livers of mice with ALF induced by LPS or D-galactosamine + TNF-α, and was associated with IL-6/TNF-α expression (70). Therefore, miR-155 may also be used as a therapeutic target for liver failure.