Liver fibrosis and repair: immune regulation of wound healing in a solid organ

Abstract

Fibrosis is a highly conserved and co-ordinated protective response to tissue injury. The interaction of multiple pathways, molecules and systems determines whether fibrosis is self-limiting and homeostatic, or whether it is uncontrolled and excessive. Immune cells have been identified as key players in this fibrotic cascade, with the capacity to exert either injury-inducing or repair-promoting effects. A multi-organ approach was recently suggested to identify the core and regulatory pathways in fibrosis, with the aim of integrating the wealth of information emerging from basic fibrosis research. In this Review, we focus on recent advances in liver fibrosis research as a paradigm for wound healing in solid organs and the role of the immune system in regulating and balancing this response.

Neutrophils alleviate fibrosis in the CCl4‐induced mouse chronic liver injury model

“…As MMPs are critically involved in the resolution of fibrosis,1 we examined the expression of Mmp s and found that Trib1 ‐deficient liver exhibited a marked increase of Mmp8 (collagenase) and Mmp9 (gelatinase B) whereas the expression level of Mmp13 , an interstitial collagenase, was unchanged (Fig. 1E).…”

“…In the liver, chronic inflammation induced by a variety of causes, such as hepatitis virus, alcohol, drugs, and immune and metabolic disorders, accompanies fibrosis that often advances to cirrhosis 1. Damaged hepatocytes release factors that activate hepatic stellate cells (HSCs) directly and indirectly by nonparenchymal cells.…”

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

“…The induction of proinflammatory cytokines during early exposure (Tx1-Tx7) mimics some features of the classic wound-healing response (Pellicoro et al, 2014), with a surge in the production of proinflammatory cytokines that drive tissue remodeling and regeneration and may aid in the formation of a cohesive tissuelike mass after bioprinting. It is likely that both the HSC and EC components of the bioprinted tissues contributed to the elevations of IL-6 and IL-8, which enhance EC survival, proliferation, angiogenesis, and recruitment of inflammatory cells during wound healing (Qazi et al, 2011).…”

“…While inflammation typically precedes or accompanies liver fibrosis and is recognized as a driver of fibrogenesis (Czaja, 2014;Pellicoro et al, 2014), the precise role of KCs in mediating this process remains elusive. This is largely due to the inability to target specific macrophage subpopulations (Tacke and Zimmermann, 2014), a question which can be addressed using this model.…”

“…Because inflammation is closely tied to fibrogenesis (Pellicoro et al, 2014), the abundance of pro-and anti-inflammatory cytokines (pg/mL) released into the culture medium from treated tissues throughout the exposure period (ie, alternate treatment days) was measured. A general decrease in cytokines starting at Tx1 is apparent for all treatment groups including vehicletreated control ( Supplementary Fig.…”