CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice

Abstract

Experimental T-cell-mediated hepatitis induced by concanavalin A (Con A) involves the production of different cytokines and chemokines and is characterized by leukocyte infiltration. Because the chemokine receptor CCR5 and its ligands (CCL3, CCL4, and CCL5) regulate leukocyte chemotaxis and activation, we investigated the role of CCR5 during Con A-induced liver injury. Serum levels of CCR5 ligands and their hepatic transcript levels were significantly increased after Con A injection, whereas CCR5 ؉ liver mononuclear cells were recruited to the liver. CCR5-deficient (CCR5 ؊/؊ ) mice disclosed increased mortality and liver injury following Con A administration compared with wild-type mice. CCR5 ؊/؊ mice also exhibited increased production of interleukin 4, tumor necrosis factor ␣, CCL3, CCL4, and CCL5, and a prominent liver mononuclear cell infiltrate, among which many cells were CCR1 ؉ . In vivo neutralization of CCR5 ligands in CCR5 ؊/؊ mice afforded a protection against hepatitis only when CCL5 was neutralized. In conclusion, CCR5 deficiency exacerbates T-cell-mediated hepatitis, and leads to increased levels of CCR5 ligands and a more pronounced liver mononuclear infiltrate, suggesting that CCR5 expression can modulate severity of immunomediated liver injury. (HEPATOLOGY 2005;42:854-862.)

Hepatic Serum Amyloid A1 Aggravates T Cell-mediated Hepatitis by Inducing Chemokines via Toll-like Receptor 2 in Mice

“…Chemokine expression is up-regulated in areas of tissue injury, and their increased expression leads to infiltration of immune cells such as lymphocytes, neutrophils, and monocytes. Chemokines and chemokine receptors play critical roles in liver diseases such as hepatitis (17)(18)(19). Chemokines are secreted from immune cells and primary cells, including hepatocytes, Kupffer cells, and endothelial cells (20).…”

Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study

“…7,8 Preliminary results from our laboratory also suggest that CCR5-deficient mice disclose higher susceptibility to experimental pancreatitis. 9 This may explain why CCR5-⌬32 mutation represents only a small minority of the population in most parts of the world.The recent observation of a hepatotoxic adverse event in patients treated with CCR5 inhibitors is consistent with our experimental observations. As pointed by S. Mauss and M. Puoti, HIV patients are frequently exposed to other hepatotoxic agents (virus, alcohol, drugs).…”

“…7,8 Preliminary results from our laboratory also suggest that CCR5-deficient mice disclose higher susceptibility to experimental pancreatitis. 9 This may explain why CCR5-⌬32 mutation represents only a small minority of the population in most parts of the world.…”

CCR5 deficiency exacerbates T-cell-mediated hepatitis in mice — Clinical implications for CCR5 inhibition as antiretroviral therapy

“…In this context, the paper by Moreno and colleagues provides an intriguing hypothesis. 1 The results from the paper suggest an increased vulnerability to hepatotoxic agents due to CCR5 deficiency or pharmacological inhibition due to an imbalance in the cytokine response rather than a direct hepatotoxic action of the drug itself.…”

“…1 This observation is of particular interest as CCR5 inhibitors are currently studied as antiretroviral drugs for the treatment of HIV infection. 2,3 However, the development of aplaviroc was stopped recently due to hepatotoxic adverse events associated with jaundice observed in four study participants.…”