ABSTRACT
Acute kidney injury (AKI) is a major worldwide health concern that currently lacks effective medical treatments. PSMP is a damage-induced chemotactic cytokine that acts as a ligand of CCR2 and has an unknown role in AKI. We have observed a significant increase in PSMP levels in the renal tissue, urine, and plasma of patients with AKI. PSMP deficiency improved kidney function and decreased tubular damage and inflammation in AKI mouse models induced by kidney ischemia-reperfusion injury, glycerol, and cisplatin. Single-cell RNA sequencing analysis revealed that Ly6Chi or F4/80lo infiltrated macrophages (IMs) were a major group of proinflammatory macrophages with strong CCR2 expression in AKI. We observed that PSMP deficiency decreased CCR2+Ly6Chi or F4/80lo IMs and inhibited M1 polarization in the AKI mouse model. Moreover, overexpressed human PSMP in the mouse kidney could reverse the attenuation of kidney injury in a CCR2-dependent manner, and this effect could be achieved without CCL2 involvement. Extracellular PSMP played a crucial role, and treatment with a PSMP-neutralizing antibody significantly reduced kidney injury in vivo. Therefore, PSMP might be a therapeutic target for AKI, and its antibody is a promising therapeutic drug for the treatment of AKI.
Subject(s)
Acute Kidney Injury , Disease Models, Animal , Macrophages , Receptors, CCR2 , Animals , Humans , Male , Mice , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Kidney/metabolism , Kidney/pathology , Macrophages/metabolism , Mice, Knockout , Receptors, CCR2/metabolism , Receptors, CCR2/genetics , Reperfusion Injury/metabolism , Neoplasm ProteinsABSTRACT
BACKGROUND & AIMS: C-C motif chemokine receptor 2 (CCR2) has been recognized as a promising target for the treatment of liver fibrosis. PC3-secreted microprotein (PSMP)/microseminoprotein (MSMP) is a novel chemotactic cytokine and its receptor is CCR2. In the present study we investigated the expression and role of PSMP in liver fibrosis/cirrhosis. METHODS: PSMP expression was studied in patients with fibrosis/cirrhosis and in 3 murine models of liver fibrosis, including mice treated with carbon tetrachloride (CCl4), bile-duct ligation, or a 5-diethoxycarbonyl-1,4-dihydrocollidine diet. The role of PSMP was evaluated in Psmp-/- mice and after treatment with a PSMP antibody in wild-type mice. The direct effects of PSMP on macrophages and hepatic stellate cells were studied in vitro. RESULTS: In this study, we found that PSMP was highly expressed in fibrotic/cirrhotic tissues from patients with different etiologies of liver disease and in the 3 experimental mouse models of fibrosis. Damage-associated molecular pattern molecules HMGB-1 and IL-33 induced hepatocytes to produce PSMP. PSMP deficiency resulted in a marked amelioration of hepatic injury and fibrosis. In CCl4-induced hepatic injury, the infiltration of macrophages and CCR2+ monocytes into the liver was significantly decreased in Psmp-/- mice. Consistent with the decreased levels of intrahepatic macrophages, proinflammatory cytokines were significantly reduced. Moreover, adeno-associated virus-8 vectors successfully overexpressing human PSMP in Psmp-/- mouse livers could reverse the attenuation of liver injury and fibrosis induced by CCl4 in a CCR2-dependent manner. Treatment with a specific PSMP-neutralizing antibody, 3D5, prevented liver injury and fibrosis induced by CCl4 in mice. At the cellular level, PSMP directly promoted M1 polarization of macrophages and activation of LX-2 cells. CONCLUSION: PSMP enhances liver fibrosis through its receptor, CCR2. PSMP is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis. LAY SUMMARY: Our present study identifies the essential role of the protein PSMP for the development and progression of liver fibrosis in humans and mice. PSMP promotes liver fibrosis through inflammatory macrophage infiltration, polarization and production of proinflammatory cytokines, as well as direct activation of hepatic stellate cells via its receptor CCR2. A PSMP antibody can significantly reduce liver fibrosis development in vivo. These findings indicate that PSMP is a potential therapeutic target and its antibody is a potential therapeutic agent for the treatment of liver fibrosis.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Liver Cirrhosis, Experimental/metabolism , Liver Neoplasms/metabolism , Neoplasm Proteins/deficiency , Receptors, CCR2/deficiency , Receptors, CCR2/metabolism , Animals , Antibodies, Neutralizing/therapeutic use , Carbon Tetrachloride/adverse effects , Carcinoma, Hepatocellular/pathology , Cell Polarity/genetics , Cells, Cultured , Cytokines/biosynthesis , Genetic Vectors , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Humans , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/prevention & control , Liver Neoplasms/pathology , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Knockout , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Neoplasm Proteins/pharmacology , Receptors, CCR2/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Treatment Outcome , Up-RegulationABSTRACT
Chemokines are a family of cytokines that orchestrate the migration and positioning of immune cells within tissues and are critical for the function of the immune system. CCR2 participates in liver pathology, including acute liver injury, chronic hepatitis, fibrosis/cirrhosis, and tumor progression, by mediating the recruitment of immune cells to inflammation and tumor sites. Although a variety of chemokines have been well studied in various diseases, there is no comprehensive review presenting the roles of all known chemokine ligands of CCR2 (CCL2, CCL7, CCL8, CCL12, CCL13, CCL16, and PSMP) in liver disease, and this review aims to fill this gap. The introduction of each chemokine includes its discovery, its corresponding chemotactic receptors, physiological functions and roles in inflammation and tumors, and its impact on different immune cell subgroups.
Subject(s)
Liver Diseases , Neoplasms , Chemokines , Fibrosis , Humans , Inflammation , Ligands , Receptors, CCR2ABSTRACT
The mechanisms of the hypercoagulable state in cirrhotics with and without hepatocellular carcinoma are incompetently comprehended. Objective: We aimed to explore the plasma Annexin A5/PS + MP ratio in these patients. Higher levels of Annexin A5 and PhosphatidylSerine bearing microparticles have been observed in cases of inflammation and increased coagulation but there are no studies which explore if there is an association between them and PVT in cirrhotics with and without HCC. So, our goal is to estimate their role in predicting PVT within HCV cirrhotics with and without HCC. 91 HCV cirrhotics with and without HCC and 20 healthy people (controls) were enlisted. Cirrhotics with and without HCC who developed PVT displayed higher levels of PS + MPs and lower Annexin A5/PS + MPs ratio (38.73 ± 1.92) and (0.00238 ± 0.00047) than cirrhotics who didn't develop PVT (22.19 ± 10.58) and (0.00451 ± 0.0023) (P < 0.001). Among the tested factors, lower Annexin A5/PS + MPs ratio show higher performance in predicting PVT in total cirrhotics, AUC, 0.919 followed by PS + MPs level, 0.876, Portal flow velocity, 0.842, Plasma Annexin A5 level, 0.509. In our hypothesis, As phosphatidylserine exposure increase due to increased level of circulating microparticles in cirrhotics with and without HCC, anenxin-A5 may be secreted by platelets and endothelial cells into the circulation as a physiological response to inactivate the elevated levels of PS bearing MPs produced in these patients but the increase in anenxin-A5 level isn't equivalent to the increase in PS bearing MPs levels. The equilibrium between plasma annexin A5 and PS bearing MPs levels is defected.
ABSTRACT
INTRODUCTION: Preoperative planning of mandibular reconstruction has moved from mechanical simulation by dental model casts or stereolithographic models into an almost completely virtual environment. CAD/CAM applications allow a high level of accuracy by providing a custom template-assisted contouring approach for bone flaps. However, the clinical accuracy of CAD reconstruction is limited by the use of prebent reconstruction plates, an analogue step in an otherwise digital workstream. TECHNICAL REPORT: In this paper the integration of computerized, numerically-controlled (CNC) milled, patient-specific mandibular plates (PSMP) within the virtual workflow of computer-assisted mandibular free fibula flap reconstruction is illustrated in a clinical case. Intraoperatively, the bone segments as well as the plate arms showed a very good fit. Postoperative CT imaging demonstrated close approximation of the PSMP and fibular segments, and good alignment of native mandible and fibular segments and intersegmentally. Over a follow-up period of 12 months, there was an uneventful course of healing with good bony consolidation. CONCLUSION: The virtual design and automated fabrication of patient-specific mandibular reconstruction plates provide the missing link in the virtual workflow of computer-assisted mandibular free fibula flap reconstruction.