Role Of Allograft Inflammatory Factor-1 Research Articles

Type I/II Immune Balance Contributes to the Protective Effect of AIF-1 on Hepatic Immunopathology Induced by Schistosoma japonicum in a Transgenic Mouse Model.

Schistosomiasis is the second most debilitating neglected tropical disease in the world. Liver egg granuloma and fibrosis are the main damage of schistosomiasis. In this study, the role of allograft inflammatory factor-1 (AIF-1) in liver pathology and its regulation in immune responses were investigated in a transgenic mouse infected with Schistosoma japonicum. We found that AIF-1 overexpression reduced worm burden and decreased egg granuloma sizes and serum alanine aminotransferase levels, along with inhibited hepatic collagen deposition and serum hydroxyproline levels during S. japonicum infection. Moreover, AIF-1 overexpression resulted in an increased ratio of Th1/Th2, increased levels of IFN-γ and T-bet, and lower levels of GATA-3 in the spleen, accompanied by increased M1 percentages, decreased M2 percentages, and thus a higher ratio of M1/M2 in the peritoneal cavity and liver. AIF-1 induced CD68 and iNOS mRNA expression and protein levels of cytoplasmic p-P38 and nuclear NF-κB, along with enhanced levels of TNF-α and TGF-β in macrophages in vitro. Moreover, the hepatic pathology had a negative correlation with Th1/Th2 and M1/M2 ratios in the infected mice. The findings reveal that the beneficial role of AIF-1 in alleviating hepatic damage is related to restoring type I/II immune balance in S. japonicum infection.

Allograft inflammatory factor-1 enhances inflammation and oxidative stress via the NF-κB pathway of bladder urothelium in diabetic rat model

ObjectivesTo explore the role of allograft inflammatory factor-1 (AIF-1) both in diabetic rat bladder urothelium and in high-glucose-treated human urothelial cell line (SV-HUC-1). MethodsInflammation and oxidative stress (OS) promote diabetic cystopathy (DCP), but the mechanisms are not fully understood. The expression level of AIF-1 in diabetic rat bladder urothelium and in the SV-HUC-1 cells treated with high glucose was detected using tissue immunofluorescence, immunohistochemistry and western blot assays. AIF-1 was knocked down and NF-κB was suppressed with the specific inhibitor BAY 11–7082 in high-glucose-treated SV-HUC-1 cells. ResultsHigh-glucose condition induced AIF-1 upregulation in vivo and in vitro. The up-regulated AIF-1 induced the production of inflammatory factors IL-6 and TNF-α and elevation of ROS. Informatics analysis suggested that NF-κB pathway is implicated in DCP. Through knockdown of AIF-1, we confirmed that AIF-1 simulated NF-κB pathway by enhancing the phosphorylation of IκB (p-IκB) and promoting the translocation of NF-κB p65 from cytoplasm into nucleus. Additionally, High-glucose-induced inflammation in SV-HUC-1 cells was attenuated by the addition of NF-κB inhibitor. ConclusionsThis study provides novel information to understand the molecular regulation mechanisms of AIF-1 in DCP.

AIF1: Function and Connection with Inflammatory Diseases.

Macrophages are a type of immune cell distributed throughout all tissues of an organism. Allograft inflammatory factor 1 (AIF1) is a calcium-binding protein linked to the activation of macrophages. AIF1 is a key intracellular signaling molecule that participates in phagocytosis, membrane ruffling and F-actin polymerization. Moreover, it has several cell type-specific functions. AIF1 plays important roles in the development of several diseases: kidney disease, rheumatoid arthritis, cancer, cardiovascular diseases, metabolic diseases and neurological disorders, and in transplants. In this review, we present a comprehensive review of the known structure, functions and role of AIF1 in inflammatory diseases.

The Role of AIF-1 in the Aldosterone-Induced Vascular Calcification Related to Chronic Kidney Disease: Evidence From Mice Model and Cell Co-Culture Model.

Increasing evidence suggests that aldosterone (Aldo) plays an essential role in vascular calcification which is a serious threat to cardiovascular disease (CVD) developed from chronic kidney disease (CKD). However, the exact pathogenesis of vascular calcification is still unclear. First, we established CKD-associated vascular calcification mice model and knockout mice model to investigate the causal relationship between allograft inflammatory factor 1 (AIF-1) and vascular calcification. Then, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) co-culture experiments were performed to further explore the mechanisms of calcification. The results of the Aldo intervention mice model and transgenic mice model showed that Aldo could cause calcification by increasing the AIF-1 level. The results of in vitro co-culture model of ECs and VSMCs showed that AIF-1 silence in ECs may alleviate Aldo-induced calcification of VSMCs. In conclusion, our study indicated that Aldo may induce vascular calcification related to chronic renal failure via the AIF-1 pathway which may provide a potential therapeutic target.

Retraction: The Role of Allograft Inflammatory Factor-1 in the Effects of Experimental Diabetes on B Cell Functions in the Heart.

[This retracts the article DOI: 10.3389/fcvm.2018.00126.].

Allograft inflammatory factor-1 in myeloid cells drives autoimmunity in type 1 diabetes.

Allograft inflammatory factor-1 (AIF1) is a calcium-responsive cytoplasmic scaffold protein that directs hematopoiesis and immune responses within dendritic cells (DC) and macrophages. Although the role of AIF1 in transplant rejection and rheumatoid arthritis has been explored, little is known about its role in type 1 diabetes. Here, we show that in vivo silencing of AIF1 in NOD mice restrained infiltration of immune cells into the pancreas and inhibited diabetes incidence. Analyses of FACS-sorted CD45neg nonleukocyte populations from resected pancreatic islets showed markedly higher expression of insulin in the AIF1-silenced groups. Evaluation of CD45+ leukocytes revealed diminished infiltration of effector T cells and DC in the absence of AIF1. Transcriptional profiling further revealed a marked decrease in cDC1 DC-associated genes CD103, BATF3, and IRF8, which are required for orchestrating polarized type 1 immunity. Reduced T cell numbers within the islets were observed, with concomitant lower levels of IFN-γ and T-bet in AIF1-silenced cohorts. In turn, there was a reciprocal increase in functionally suppressive pancreas-resident CD25+Foxp3+CD4+ Tregs. Taken together, results show that AIF1 expression in myeloid cells plays a pivotal role in promoting type 1 diabetes and that its suppression restrains insulitis by shifting the immune microenvironment toward tolerance.

Allograft Inflammatory Factor-1 Governs Hematopoietic Stem Cell Differentiation Into cDC1 and Monocyte-Derived Dendritic Cells Through IRF8 and RelB in vitro.

The multistep differentiation process from hematopoietic stem cells through common myeloid progenitors into committed dendritic cell (DC) subsets remains to be fully addressed. These studies now show that Allograft Inflammatory Factor-1 (AIF1) is required for differentiation of classical DC type 1 (cDC1) subsets and monocyte-derived DC (Mo-DC). Phenotypic studies found that AIF1 expression increased in committed subsets differentiating from common myeloid progenitors (CMP). However, silencing AIF1 expression in hematopoietic stem progenitors restrained the capacity to differentiate into Mo-DC and cDC1 cell subsets under GM-CSF or Flt3-L stimuli conditions, respectively. This was further marked by restrained expression of IRF8, which is critical for development of Mo-DC and cDC1 subsets. As a result, absence of AIF1 restrained the cells at the Lin−CD117+FcγR−CD34+ CMP stage. Further biochemical studies revealed that abrogating AIF1 resulted in inhibition of the NFκB family member RelB expression and p38 MAPK phosphorylation during differentiation of Mo-DC. Lastly, protein binding studies identified that AIF1 interacts with protein kinase C (PKC) to influence downstream signaling pathways. Taken together, this is the first report showing a novel role of AIF1 as a calcium-responsive scaffold protein that supports IRF8 expression and interacts with PKC to drive NFκB-related RelB for successfully differentiating hematopoietic progenitor cells into cDC and Mo-DC subsets under Flt3-L and GM-CSF stimuli, respectively.

The Role of Allograft Inflammatory Factor-1 in the Effects of Experimental Diabetes on B Cell Functions in the Heart.

Diabetes mellitus (DM) often causes chronic inflammation, hypertrophy, apoptosis and fibrosis in the heart and subsequently leads to myocardial remodeling, deteriorated cardiac function and heart failure. However, the etiology of the cardiac disease is unknown. Therefore, we assessed the gene expression in the left ventricle of diabetic and non-diabetic mice using Affymetrix microarray analysis. Allograft inflammatory factor-1 (AIF-1), one of the top downregulated B cell inflammatory genes, is associated with B cell functions in inflammatory responses. Real-time reverse transcriptase-polymerase chain reaction confirmed the Affymetrix data. The expression of CD19 and AIF-1 were downregulated in diabetic hearts as compared to control hearts. Using in vitro migration assay, we showed for the first time that AIF-1 is responsible for B cell migration as B cells migrated to GFP-AIF-1-transfected H9C2 cells compared to empty vector-transfected cells. Interestingly, overexpression of AIF-1 in diabetic mice prevented streptozotocin-induced cardiac dysfunction, inflammation and promoted B cell homing into the heart. Our results suggest that AIF-1 downregulation inhibited B cell homing into diabetic hearts, thus promoting inflammation that leads to the development of diabetic cardiomyopathy, and that overexpression of AIF-1 could be a novel treatment for this condition.

Role of allograft inflammatory factor-1 in bleomycin-induced lung fibrosis

Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries in a rat ectopic cardiac allograft model. We previously reported that AIF-1 is associated with the pathogenesis of rheumatoid arthritis and skin fibrosis in sclerodermatous graft-versus-host disease mice. Here, we used an animal model of bleomycin-induced lung fibrosis to analyze the expression of AIF-1 and examine its function in lung fibrosis. The results showed that AIF-1 was expressed on lung tissues, specifically macrophages, from mice with bleomycin-induced lung fibrosis. Recombinant AIF-1 increased the production of TGF-β which plays crucial roles in the mechanism of fibrosis by mouse macrophage cell line RAW264.7. Recombinant AIF-1 also increased both the proliferation and migration of lung fibroblasts compared with control group. These results suggest that AIF-1 plays an important role in the mechanism underlying lung fibrosis, and may provide an attractive new therapeutic target.

AIF1 expression regulates differentiation of dendritic cells from hematopoietic stem cell multipotent progenitor subsets and regulates antigen presentation capacity

Abstract Dendritic cells (DC) are indispensable in orchestrating adaptive immunity, serving as the principal messengers between innate and adaptive arms. DC subsets are derived from CD34+ hematopoietic stem cells (HSC). DC development progress through differentiation from HSC multipotent progenitors towards common myeloid progenitors. However, additional proteins involved in this selective differentiation process remain to be identified. For these studies, use of transcriptomic profiling and RNA interference (RNAi) approaches have now identified that Allograft Inflammatory Factor-1 (AIF1) directly contributes to DC differentiation and immunomodulatory processes. HSC multipotent progenitors, identified as CD117+Lin-CD34+SCA1+, were found to not express AIF1. However, CD117+Lin-CD34+SCA1- and CD117+Lin-CD34-SCA1- subsets, known as the oligopotent progenitors, did express AIF1. Importantly, this was restricted to common myeloid progenitors, as the common lymphoid progenitors, defined as CD117+Lin-SCA1-IL-7Rα+ did not express AIF1. RNAi knockdown of AIF1 in sorted Lin-CD34−CD117+SCA1+ cells led to restrained differentiation in DC upon culturing with GM-CSF. Interestingly, knockdown of AIF1 in committed CD11c+ DC resulted in impaired antigen presentation to cognate CD4+ T cells in vitro, suggesting an important immunostimulatory role in committed myeloid lineages. Current studies are now adoptively transferring HSC knocked out for AIF1 into mice to assess in vivo DC differentiation ability and capacity to migrate and populate the splenic compartment. This is the first report showing the novel role of AIF1 in dendritic cell development and antigen presentation.

The immunologic function and role of allograft inflammatory factor-1

Allograft inflammatory factor-1 is the protein that expressed in the macrophages around the coronary arteries in rat ectopic cardiac allograft model. AIF-1 is produced mainly by macrophages and regulated by interferon-gamma (IFN-γ). There are various splicing valiants in AIF-1, and the functions are different. AIF-1 has Ca-binding EF-hand motif that induces cell proliferation and migration by structural features. Besides cell proliferation and migration, AIF-1 contributes to secretion of inflammatory cytokines and chemokines such as IL-6, IL-10, IL-12, and transforming growth factor-beta (TGF-β), insulin resistance by downregulation of GLUT4 or IRS-1, and fibrosis process by upregulation of collagen production. It has been elucidated that AIF-1 is responsible for the onset of various diseases such as rheumatoid arthritis and systemic sclerosis, atherosclerotic disease, diabetes mellitus. AIF-1 may have the therapeutic potential for chronic inflammatory diseases by elucidation of the mechanism.

Ursolic Acid Induces Allograft Inflammatory Factor-1 Expression via a Nitric Oxide-Related Mechanism and Increases Neovascularization

Ursolic acid (UA), a triterpenoid compound found in plants, is used in the human diet and in medicinal herbs and possesses a wide range of biological benefits including antioxidative, anti-inflammatory, and anticarcinogenic effects. Endothelial expression of allograft inflammatory factor-1 (AIF-1) mediates vasculogenesis, and nitric oxide (NO) produced by endothelial NO (eNOS) represents a mechanism of vascular protection. It is unclear whether UA affects the neovascularization mediated by AIF-1 and eNOS expression. This study investigated the effects and mechanisms of UA on angiogenesis in vivo in hind limb ischemic animal models and in vitro in human coronary artery endothelial cells (HCECs). This study explored the impact of UA on endothelial cell (EC) activities in vitro in HCECs, vascular neovasculogenesis in vivo in a mouse hind limb ischemia model, and the possible role of AIF-1 in vasculogenesis. The results demonstrate that UA enhances collateral blood flow recovery through induction of neovascularization in a hind limb ischemia mouse model. In vitro data showed that UA increases tube formation and migration capacities in human endothelial cells, and exposing HCECs to UA increased AIF-1 expression through a NO-related mechanism. Moreover, UA administration increased capillary density and eNOS and AIF-1 expression in ischemic muscle. These findings suggest that UA may be a potential therapeutic agent in the induction of neovascularization and provide a novel mechanistic insight into the potential effects of UA on ischemic vascular diseases.

Expression of allograft inflammatory factor-1 and CD68 in haemangioma: implication in the progression of haemangioma

Recent studies revealed that immune and immune-mediated inflammatory events may contribute to the pathogenesis of haemangioma. As a modulator of immune responses, the allograft inflammatory factor-1 (AIF-1) is involved in immune dysfunction and macrophage activation. To investigate the possible role of AIF-1 in the progression of haemangioma. In a retrospective study of haemangiomas in the oral and facial regions, we assessed lesional immunoreactivities for AIF-1, CD68 and Ki67. Negative controls were similarly confirmed, including 24 pyogenic granulomas, 26 vascular malformations, five samples of normal skin, 10 squamous cell carcinomas of the tongue and three placentas. Immunostaining for each antigen in the haemangiomas was compared with control tissues. Out of all the samples, intense immunoreactivity for AIF-1 was detected in 17 of 19 (89%) haemangioma specimens, with a specific location in the endothelial cells. The intensity of AIF-1 immunostaining did not show remarkable difference among proliferating, involuting and involuted haemangiomas. CD68-positive endothelial cells were found in the neovessels of haemangiomas, as well as in pyogenic granulomas and squamous cell carcinoma. The exclusive expression of AIF-1 on endothelial cells of haemangiomas suggests that it may play a significant role in the pathophysiology and progression of haemangiomas. AIF-1 can be used as an additional biomarker for infantile haemangiomas. CD68-positive cells participate in the neovessel formation during proliferative haemangioma and contribute to the promotion of haemangioma growth.

Potential roles of allograft inflammatory factor-1 in the pathogenesis of hemangiomas

Hemangiomas are benign tumors of the vascular endothelium and are the most common tumors of infancy. These tumors are characterized by an initial phase of rapid proliferation in the first months of life, which is followed, in most cases, by spontaneous slow involution. Despite their high prevalence, their detailed pathogenesis remains unknown. Recent studies suggest that immunity responses, inflammatory cells and their precursors, myeloid cells, play important roles in the growth and involution of hemangiomas. The allograft inflammatory factor-1 is a powerful gene that is involved in several kinds of inflammatory response-related diseases. Studies also show that it is implicated in angiogenesis, proliferation and differentiation of stem cells, and development of tumors. Taken all these evidences into consideration, we hypothesize that allograft inflammatory factor-1 plays potential roles in pathogenesis, proliferation and involution of hemangioma. Investigating the role of allograft inflammatory factor-1 in the proliferation and involution of hemangioma will lead to a better understanding of pathogenesis of this lesion. Furthermore, the subtle regulation of allograft inflammatory factor-1 in the involution of hemangiomas will help design a new anti-angiogenic therapy for some tumors.

Allograft inflammatory factor-1 (AIF-1) is crucial for the survival and pro-inflammatory activity of macrophages

Our previous studies revealed that macrophages played an important role in linking injury, inflammatory and immune response in small-for-size liver transplantation. However, the molecular basis that promoted macrophage activation was not clear. In the present study, we explored the potential role of allograft inflammatory factor-1 (AIF-1) in mediating the survival and pro-inflammatory activity of macrophages in a macrophage cell line. First, the expression of AIF-1 was investigated with the stimulation of pro-inflammatory cytokines and anti-inflammatory treatment. Second, the level of inducible nitric oxide synthase (iNOS) and the survival and migration activity of macrophages were determined with the alterations of AIF-1 expression. Finally, a potential molecule that regulated AIF-1 expression was identified by the proteomic approach. The macrophage cell line expressed a certain level of endogenous AIF-1, which could be enhanced by pro-inflammatory cytokines IL-1beta or tumor necrosis factor-alpha and suppressed by anti-inflammatory drug sodium salicylate. AIF-1 augmentation induced by AIF-1/PCDNA3.1(+) transfection enhanced the levels of iNOS and monocyte chemoattractant protein-1, and promoted the cell migration. On the other hand, suppression of AIF-1 expression by AIF-1/short interference RNA (siRNA) inhibited iNOS production, induced macrophage cell apoptosis and blocked the cell migration. Using two-dimensional electrophoresis, a disintegrin and metalloproteinase domain 3 (ADAM3) was identified after AIF-1/siRNA transfection. Transfection of ADAM3/PCDNA3.1(+) up-regulated the expression of AIF-1 and iNOS, whereas suppression of ADAM3 expression down-regulated AIF-1 and iNOS expression. In conclusion, AIF-1 played an important role in the survival and pro-inflammatory activity of macrophages, and ADAM3 might be an upstream molecule that regulated AIF-1 expression.

The Role of Allograft Inflammatory Factor-1 in Development of Coronary Artery Vasculopathy.

Allograft inflammatory factor-1 (AIF-1) is a 143-amino acid, cytoplasmic, calcium- binding protein that is expressed in a variety of inflammatory situations. Constitutively expressed in leukocytes, AIF-1 is not expressed in unstimulated vascular smooth muscle cells (VSMCs), but is strongly induced in response to injury and inflammatory cytokines. Overexpression of AIF-1 in VSMCs promotes their proliferation by dysregulation of cell cycle protein expression and subsequent shortening of the cell cycle. In cardiac transplant recipients, the expression of AIF-1 mRNA in cardiac allografts correlates with rejection, and the amount of AIF-1 expressed is proportional to the severity of rejection. AIF-1 is expressed in coronary arteries with cardiac allograft vasculopathy, and persistent expression of AIF-1 in the allograft correlates with development of cardiac allograft vasculopathy. The current hypothesis is that the expression of AIF-1 in injured arteries may participate in the progression of cardiac allograft vasculopathy by its ability to promote growth of VSMCs, implicating AIF-1 as a target for treating proliferative arteriopathies. (c) 2002 Prous Science. All rights reserved.