Tissue-Specific Regulation of p38α-Mediated Inflammation in Con A–Induced Acute Liver Damage

Abstract

Because p38α plays a critical role in inflammation, it has been an attractive target for the development of anti-inflammation therapeutics. However, p38α inhibitors showed side effects including severe liver toxicity that often prevailed over the benefits in clinical studies, and the mechanism of toxicity is not clear. Here, we demonstrate that p38α regulates the inflammatory responses in the acute liver inflammation in a tissue-specific manner, and liver toxicity by p38α inhibitors may be resulted from the inhibition of protective activity of p38α in the liver. Genetic ablation of p38α in T and NKT cells protected mice from the liver injury in ConA-induced liver inflammation, while liver-specific deletion of p38α aggravated the liver pathology. We found that p38α deficiency in the liver increased the expression of chemokines to recruit more inflammatory cells, indicating that p38α in the liver plays a protective anti-inflammatory role during acute liver inflammation. Therefore, our results suggest that p38α regulates the inflammatory responses in a tissue-specific manner, and that the tissue-specific p38α targeting strategies can be used for the development of an effective anti-inflammation treatment with an improved side-effect profile.

Role of P38 MAPK in Bile Formation and Cholestasis

“…Clinical trials with certain p38 MAPK inhibitors were discontinued because of liver toxicity [117,125], which is likely to be due to the inhibition of p38α MAPK. This is consistent with studies suggesting that deficiency of p38α in the liver increases the expression of chemokines to recruit more inflammatory cells [126], facilitates N-Nitrosodiethylamine (DEN) -induced hepatocellular carcinoma and increased proliferation [127,128]. In addition, p38α MAPK facilitates bile formation by translocating MRP2 to the PM.…”

The Opposite Expected Effect of p38 Inhibitors on Fat Graft Survival

“…It is activated by stress, playing an important role also in immune response and in the regulation of cell survival, differentiation, and apoptosis induction. 14 – 16 p38 inhibitors are being sought for possible therapeutic effect on acute liver disease, 17 prostate 18 and esophageal cancer, 19 autoimmune diseases, and other inflammatory processes, 14 – 16 for example, pamapimod. 20 For chronic obstructive pulmonary disease and asthma, numerous clinical trials have even been performed with promising results, 21 – 23 for example, dilmapimod.…”

Hepatospecific ablation of p38α MAPK governs liver regeneration through modulation of inflammatory response to CCl4-induced acute injury

“…In addition, we clearly identified that Ccl2/Ccl5 chemotactic signals were crucial in that response as their neutralization sensitized to increase liver injury. Therefore, our findings highlight a new aspect in the pleiotropic role of p38α in hepatocytes during acute liver injury, as until now the beneficial effect of p38α deletion was strictly observed when performed in immune effectors such as liver myeloid cells or T/NKT cells 51,52 . Furthermore, the work of Kang and collaborators provided evidence that p38α ablation in hepatocytes was fueled by a drastic accentuation of liver injury associated with a massive inflammatory cell recruitment 51 .…”

“…In the present study, we developed a new inducible and hepatospecific mice model in which p38α isoform was completely deleted in mature hepatocytes. Until now, p38α ablation in the liver was shown as deleterious in different models of liver injury 22,25,51 . In this study, using the CCl 4 model of acute liver injury, we demonstrate for the first time that p38α deletion generated a pro-hepatoprotective response against liver injury.…”