Hepatic infiltration of neutrophils is a hallmark of steatohepatitis; however, the role of neutrophils in the progression of steatohepatitis remains unknown.
Abstract Renal macrophages (RMs) participate in tissue homeostasis, inflammation and repair. RMs consist of embryo-derived (EMRMs) and bone marrow-derived RMs (BMRMs), but the fate, dynamics, replenishment, functions and metabolic states of these two RM populations remain unclear. Here we investigate and characterize RMs at different ages by conditionally labeling and ablating RMs populations in several transgenic lines. We find that RMs expand and mature in parallel with renal growth after birth, and are mainly derived from fetal liver monocytes before birth, but self-maintain through adulthood with contribution from peripheral monocytes. Moreover, after the RMs niche is emptied, peripheral monocytes rapidly differentiate into BMRMs, with the CX3CR1/CX3CL1 signaling axis being essential for the maintenance and regeneration of both EMRMs and BMRMs. Lastly, we show that EMRMs have a higher capacity for scavenging immune complex, and are more sensitive to immune challenge than BMRMs, with this difference associated with their distinct glycolytic capacities.
Abstract graphic Interleukin‐22 ( IL ‐22) plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces by binding to the receptors IL ‐22 R 1, which is generally thought to be expressed exclusively in epithelial cells, and IL ‐10 R 2. Our laboratory previously demonstrated that IL ‐22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL ‐22 R 1 and IL ‐10 R 2. Recently, we have identified high expression levels of IL ‐22 R 1 and IL ‐10 R 2 in liver progenitor cells and hepatic stellate cells ( HSCs ). Overexpression of IL ‐22 in vivo or treatment with IL ‐22 in vitro promotes proliferation of liver progenitor cells via a signal transducer and activator of transcription 3 ( STAT 3)‐dependent mechanism. IL ‐22 treatment also prevents HSC apoptosis in vitro and in vivo . Surprisingly, overexpression of IL ‐22, via either gene targeting or exogenous administration of adenovirus expressing IL ‐22, reduces liver fibrosis and accelerates the resolution of liver fibrosis during recovery. The anti‐fibrotic effects of IL ‐22 are mediated via the activation of STAT 3 in HSCs and subsequent induction of suppressor of cytokine signaling 3, which induces HSC senescence. Taken together, the hepatoprotective, mitogenic, and anti‐fibrotic effects of IL ‐22 are beneficial in ameliorating alcoholic liver injury. Importantly, due to the restricted expression of IL ‐22 R 1, IL ‐22 therapy is expected to have few side effects, thus making IL ‐22 a potential candidate for treatment of alcoholic liver disease.
Cannabidiol (CBD) is a non-psychoactive component of marijuana, which has anti-inflammatory effects. It has also been approved by FDA for various orphan diseases for exploratory trials. Herein, we investigated the effects of CBD on liver injury induced by chronic plus binge alcohol feeding in mice. CBD or vehicle was administered daily throughout the alcohol feeding study. At the conclusion of the feeding protocol, serums samples, livers or isolated neutrophils were utilized for molecular biology, biochemistry and pathology analysis. CBD significantly attenuated the alcohol feeding-induced serum transaminase elevations, hepatic inflammation (mRNA expressions of TNFα, MCP1, IL1β, MIP2 and E-Selectin, and neutrophil accumulation), oxidative/nitrative stress (lipid peroxidation, 3-nitrotyrosine formation, and expression of reactive oxygen species generating enzyme NOX2). CBD treatment also attenuated the respiratory burst of neutrophils isolated from chronic plus binge alcohol fed mice or from human blood, and decreased the alcohol-induced increased liver triglyceride and fat droplet accumulation. Furthermore, CBD improved alcohol-induced hepatic metabolic dysregulation and steatosis by restoring changes in hepatic mRNA or protein expression of ACC-1, FASN, PPARα, MCAD, ADIPOR-1, and mCPT-1. Thus, CBD may have therapeutic potential in the treatment of alcoholic liver diseases associated with inflammation, oxidative stress and steatosis, which deserves exploration in human trials.
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