MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis

The mesencephalic astrocyte-derived neurotrophic factor(MANF)has been recently identified as a neurotrophic factor,but its role in hepatic fibrosis is unknown.Here,we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4.MANF deficiency in either hepatocytes or hepatic mono-macrophages,particularly in hepatic mono-macrophages,clearly exacerbated hepatic fibrosis.Myeloid-specific MANF knockout increased the population of hepatic Ly6C^(high)macrophages and promoted HSCs activation.Furthermore,MANF-sufficient macrophages(from WT mice)transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout(MKO)mice.Mechanistically,MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation.Pharmacologically,systemic administration of recombinant human MANF significantly alleviated CCl_(4)-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout(HKO)mice.This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a“brake”on the upstream of NF-κB pathway,which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

Circular RNA circCCNB1 inhibits the migration and invasion of nasopharyngeal carcinoma through binding and stabilizing TJP1 mRNA

Nasopharyngeal carcinoma(NPC)is a malignant tumor that usually occurs in people from Southeast Asia and Southern China.NPC is prone to migration and invasion,leading to poor prognosis.A large number of circular RNAs(circ RNAs)exacerbate the process of metastasis in NPC;however,their underlying mechanisms remain unclear.We found that the circular RNA circ CCNB1,encoded by the oncogene CCNB1,was downregulated in NPC biopsies and cell lines.In vitro assays show that circ CCNB1 inhibits NPC cell migration and invasion.Moreover,circ CCNB1 induces a protein,nuclear factor 90(NF90),to bind and prolong the half-life of tight junction protein 1(TJP1)m RNA.Upregulation of TJP1 enhances tight junctions between cancer cells and inhibits NPC cell migration and invasion.This study reveals a novel biological function of circ CCNB1 in the migration and invasion of NPC by enhancing the tight junctions of cancer cells by binding to NF90 proteins and TJP1 m RNA,and may provide a potential therapeutic target for NPC.

Biology and pathology of the uterine micro environ merit and its natural killer cells

Tissues are the new frontier of discoveries in immunology.Cells of the immune system are an integral part of tissue physiology and immunity.Determining how immune cells inhabit,housekeep,and defend gut,lung,brain,liver,uterus,and other organs helps revealing the intimate details of tissue physiology and may offer new therapeutic targets to treat pathologies.The uterine microenvironment modulates the development and function of innate lymphoid cells[ILC,largely represented by natural killer(NK)cells],macrophages,T cells,and dendritic cells.These immune cells,in turn,contribute to tissue homeostasis.Regulated by ovarian hormones,the human uterine mucosa(endometrium)undergoes ~400 monthly cycles of breakdown and regeneration from menarche to menopause,with its fibroblasts,glands,blood vessels,and immune cells remodeling the tissue into the transient decidua.Even more transformative changes occur upon blastocyst implantation.Before the placenta is formed,the endometrial glands feed the embryo by histiotrophic nutrition while the uterine spiral arteries are stripped of their endothelial layer and smooth muscle actin.This arterial remodeling is carried out by invading fetal trophoblast and maternal immune cells,chiefly uterine NK(uNK)cells,which also assist fetal growth.The tran sformed arteries no Ion ger resp ond to mater nal stimuli and meet the increasi ng dema nds of the growing fetus.This review focuses on how the everchanging uterine microenvironment affects uNK cells and how uNK cells regulate homeostasis of the decidua,placenta development,and fetal growth.Determining these pathways will help understand the causes of major pregnancy complications.