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

Abstract

Mammalian p38α MAPK (Mitogen-Activated Protein Kinase) transduces a variety of extracellular signals that regulate cellular processes, such as inflammation, differentiation, proliferation or apoptosis. In the liver, depending of the physiopathological context, p38α acts as a negative regulator of hepatocyte proliferation as well as a promotor of inflammatory processes. However, its function during an acute injury, in adult liver, remains uncharacterized. In this study, using mice that are deficient in p38α specifically in mature hepatocytes, we unexpectedly found that lack of p38α protected against acute injury induced by CCl4 compound. We demonstrated that the hepatoprotective effect alleviated ROS accumulation and shaped the inflammatory response to promote efficient tissue repair. Mechanistically, we provided strong evidence that Ccl2/Ccl5 chemokines were crucial for a proper hepatoprotective response observed secondary to p38α ablation. Indeed, antibody blockade of Ccl2/Ccl5 was sufficient to abrogate hepatoprotection through a concomitant decrease of both inflammatory cells recruitment and antioxidative response that result ultimately in higher liver damages. Our findings suggest that targeting p38α expression and consequently orientating immune response may represent an attractive approach to favor tissue recovery after acute liver injury.

Circular RNA circACSL1 aggravated myocardial inflammation and myocardial injury by sponging miR-8055 and regulating MAPK14 expression

“…p38 MAPK family of signaling proteins like p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13), are involved in the regulation of stress-induced gene activation, cytosolic chaperone activity, cell cycle, apoptosis, cell development, proliferation, and inflammatory responses 32 , 33 . Among these, p38α (MAPK14), being the most abundant and well-characterized isoform, has a central role in the stress-activated initiation of pro-inflammatory responses as well as a negative regulator of proliferation of hepatocytes during acute liver injury 34 . Downstream substrates of MAPK14 signaling cascades include transcription factors and protein kinases that dictate cellular responses to stress and inflammation 35 , 36 .…”

Investigation of Thyroid Hormone Associated Gene-Regulatory Networks during Hepatogenesis using an Induced Pluripotent Stem Cell based Model

“…Further dissecting the overlap between the T3/T4 treated cells and the mature phenotype indicated at MAPK-signaling and also the NODAL branch of TGFβ-signaling as potential actors driving maturation. These findings were underpinned by previous studies reporting possible roles of MAPK in liver maturation [30], [31] and the wellsettled role of NODAL in early liver development [32], but need further evaluation in larger studies.…”

“…Here, the results include two GOs related to MAPK/ERK signaling and the GO developmental maturation. MAPK signaling has been implicated in liver maturation particularly via p38α MAPK [30], [31]. Looking into the gene lists of these GOs most outstanding is the gene NODAL -a part of the TGFβ-signaling pathway -which was described to force cell fate into mesoderm lineage upon low NODAL expression and into endoderm upon high expression [9], [32].…”

Expression of a constitutively active p38α mutant in mice causes early death, anemia, and accumulation of immunosuppressive cells

“…However, the high phosphorylation levels of p38a D176A+F327S observed in the mice and in culture cells [40] weaken this notion. Another explanation is that, perhaps, in many tissues, abnormal p38a activity would be hazardous only under particular conditions (e.g., aging, injury, stress, drugs [16,41,42]).…”