The mechanism of low molecular weight fucoidan-incorporated nanofiber scaffolds inhibiting oral leukoplakia via SR-A/Wnt signal axis.

Oral leukoplakia (OLK) is the most common oral precancerous lesion, and 3%-17% of OLK patients progress to oral squamous cell carcinoma. OLK is susceptible to recurrence and has no effective treatment. However, conventional drugs have significant side effects and limitations. Therefore, it is important to identify drugs that target OLK. In this study, scavenger receptor A (SR-A) was found to be abnormally highly expressed in the oral mucosal epithelial cells of OLK patients, whereas molecular biology studies revealed that low molecular weight fucoidan (LMWF) promoted apoptosis of dysplastic oral keratinocytes (DOK) and inhibited the growth and migration of DOK, and the inhibitory effect of LMWF on OLK was achieved by regulating the SR-A/Wnt signaling axis and related genes. Based on the above results and the special situation of the oral environment, we constructed LMWF/poly(caprolactone-co-lactide) nanofiber membranes with different structures for the in-situ treatment of OLK using electrospinning technology. The results showed that the nanofiber membranes with a shell-core structure had the best physicochemical properties, biocompatibility, and therapeutic effect, which optimized the LMWF drug delivery and ensured the effective concentration of the drug at the target point, thus achieving precise treatment of local lesions in the oral cavity. This has potential application value in inhibiting the development of OLK.

Ozone enhances the efficacy of radiation therapy in esophageal cancer.

Radioresistance is increasingly developed in esophageal cancer. Increasing radiation sensitivity can reduce the mortality of esophageal cancer. To investigate the effect and mechanism of ozone on the radiotherapy sensitization of esophageal carcinoma. KYSE150 cells were xenografted subcutaneously into nude mice and irradiated with 8 Gy radiation according to different subgroups (sham, radiation, ozone and radiation+ozone group (n = 10 per group)). Half of the mice were used to determine the body weight, tumor size and tumor weight. Half of the mice were used to collect peripheral blood. The serum was centrifuged to detect circulating cell-free DNA (cf-DNA), interleukin-6 (IL-6), interferon-γ (IFN-γ), myeloperoxidase (MPO)-DNA complexes, tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9) and hypoxia-inducible factor-1α (HIF-1α) using commercial kits. The levels of phosphorylation AMP-activated protein kinase (p-AMPK) and scavenger receptor-A (SR-A) were measured by immunocytochemistry and Western blotting in the tumor tissues of mice. Ozone alone or combined with radiation therapy significantly reduced the body weight, tumor volume and tumor weight of esophageal cancer compared to the sham group. The ELISA results showed that the levels of cf-DNA, IFN-γ, MPO-DNA complexes, TNF-α, IL-6, HIF-1α and MMP-9 in the peripheral blood of mice treated with ozone combined with radiation were significantly lower compared with the radiation group. Ozone, synergistically with radiation, significantly increased the protein expression of p-AMPK and SR-A. Ozone may increase the radiosensitivity of esophageal cancer by inhibiting neutrophil extracellular traps.

Combination of scavenger receptor-A with anti-cyclic citrullinated peptide antibody for the diagnosis of rheumatoid arthritis.

OBJECTIVES: The routine biomarkers for rheumatoid arthritis (RA), including anticyclic citrullinated peptide antibody (anti-CCP), rheumatoid factor (RF), immunoglobulin M (IgM), erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) have limited sensitivity and specificity. Scavenger receptor-A (SR-A) is a novel RA biomarker identified by our group recently, especially for seronegative RA. Here, we performed a large-scale multicentre study to further assess the diagnostic value of SR-A in combination with other biomarkers for RA. METHODS: The performance of SR-A in combination with other biomarkers for RA diagnosis was first revealed by a pilot study, and was further elucidated by a large-scale multicentre study. A total of 1129 individuals from 3 cohorts were recruited in the study, including RA patients, healthy controls, and patients with other common rheumatic diseases. Diagnostic properties were evaluated by the covariate-adjusted receiver-operating characteristic (AROC) curve, sensitivity, specificity and clinical association, respectively. RESULTS: Large-scale multicentre analysis showed that SR-A and anti-CCP dual combination was the optimal method for RA diagnosis, increasing the sensitivity of anti-CCP by 13% (87% vs 74%) while maintaining a specificity of 90%. In early RA patients, SR-A and anti-CCP dual combination also showed promising diagnostic value, increasing the sensitivity of anti-CCP by 7% (79% vs 72%) while maintaining a specificity of 94%. Moreover, SR-A and anti-CCP dual combination was correlated with ESR, IgM, and autoantibodies of RA patients, further revealing its clinical significance. CONCLUSION: SR-A and anti-CCP dual combination could potentially improve early diagnosis of RA, thus improving the prognosis and reducing mortality.

Macrophage-expressed SRA ameliorates alcohol-induced liver injury by suppressing S-glutathionylation of Notch1 via recruiting thioredoxin.

Scavenger receptor A (SRA) is preferentially expressed in macrophages and implicated as a multifunctional pattern recognition receptor for innate immunity. Hepatic macrophages play a primary role in the pathogenesis of alcoholic liver disease. Herein, we observed that SRA expression was significantly increased in the liver tissues of mice with alcohol-related liver injury. SRA-deficient (SRA-/-) mice developed more severe alcohol-induced liver disease than wild-type mice. Enhanced liver inflammation existed in alcohol-challenged SRA-/- mice and was associated with increased Notch activation in hepatic macrophages compared with wild-type control animals. Mechanistically, SRA directly bound with Notch1 and suppressed its S-glutathionylation, thereby inhibiting Notch pathway activation. Further, we determined that the SRA interacted with thioredoxin-1 (Trx-1), a redox-active protein. SRA inhibited Trx-1 dimerization and facilitated the interaction of Trx-1 with Notch1. Application of a Trx-1-specific inhibitory agent during macrophage stimulation abolished SRA-mediated regulation of the Notch pathway and its downstream targets. In summary, our study revealed that SRA plays a critical role in macrophage inflammatory response by targeting Notch1 for its glutathionylation. SRA-mediated negative regulation of Notch activation might serve as a novel therapeutic strategy for alcohol-induced liver injury.

Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cß/store-operated calcium entry/calreticulin/scavenger receptor A pathways.

BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cß/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cß/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.

Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival.

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-ß (IFN-ß) production. UreC-mediated activation of the IFN-ß pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.

Effectiveness of Combinational Treatments for Alzheimer's Disease with Human Neural Stem Cells and Microglial Cells Over-Expressing Functional Genes.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. In AD patients, amyloid-ß (Aß) peptide-mediated degeneration of the cholinergic system utilizing acetylcholine (ACh) for memory acquisition is observed. Since AD therapy using acetylcholinesterase (AChE) inhibitors are only palliative for memory deficits without reversing disease progress, there is a need for effective therapies, and cell-based therapeutic approaches should fulfil this requirement. We established F3.ChAT human neural stem cells (NSCs) encoding the choline acetyltransferase (ChAT) gene, an ACh-synthesizing enzyme, HMO6.NEP human microglial cells encoding the neprilysin (NEP) gene, an Aß-degrading enzyme, and HMO6.SRA cells encoding the scavenger receptor A (SRA) gene, an Aß-uptaking receptor. For the efficacy evaluation of the cells, first, we established an appropriate animal model based on Aß accumulation and cognitive dysfunction. Among various AD models, intracerebroventricular (ICV) injection of ethylcholine mustard azirinium ion (AF64A) induced the most severe Aß accumulation and memory dysfunction. Established NSCs and HMO6 cells were transplanted ICV to mice showing memory loss induced by AF64A challenge, and brain Aß accumulation, ACh concentration and cognitive function were analyzed. All the transplanted F3.ChAT, HMO6.NEP and HMO6.SRA cells were found to survive up to 4 weeks in the mouse brain and expressed their functional genes. Combinational treatment with the NSCs (F3.ChAT) and microglial cells encoding each functional gene (HMO6.NEP or HMO6.SRA) synergistically restored the learning and memory function of AF64A-challenged mice by eliminating Aß deposits and recovering ACh level. The cells also attenuated inflammatory astrocytic (glial fibrillary acidic protein) response by reducing Aß accumulation. Taken together, it is expected that NSCs and microglial cells over-expressing ChAT, NEP or SRA genes could be strategies for replacement cell therapy of AD.

Macrophage scavenger receptor A1 antagonizes abdominal aortic aneurysm via upregulating IRG1.

AIMS: Abdominal aortic aneurysm (AAA) is a common, usually asymptomatic disease with high mortality and limited therapeutic options. Extensive extracellular matrix (ECM) fragmentation and transmural inflammation act as major pathological processes of AAA. However, the underlying regulatory mechanisms remain incompletely understood. Herein, we aimed to investigate the role of scavenger receptor A1 (SR-A1), a key pattern recognition receptor modulating macrophage activity, in pathogenesis of AAA. METHODS AND RESULTS: The AAA model was generated by administration of angiotensin II (Ang II) into apolipoprotein E knockout mice or peri-arterial application of calcium phosphate in C57BJ/6L mice. We found that SR-A1 was markedly down-regulated in the macrophages isolated from murine AAA aortas. Global or myeloid-specific ablation of SR-A1 aggravated vascular inflammation, loss of vascular smooth muscle cells and degradation of the extracellular matrix. These effects of SR-A1 deficiency on AAA development were mediated by suppressed immunoresponsive gene 1 (IRG1) and increased inflammatory response in macrophages. Mechanically, binding of SR-A1 with Lyn led to STAT3 phosphorylation and translocation into the nucleus, in which STAT3 promoted IRG1 transcription through directly binding to its promoter. Restoration of macrophage SR-A1 in SR-A1-deficient mice by bone marrow transplantation or administration of 4-octyl itaconate, the derivate of IRG1 product itaconate, could relieve murine AAA. CONCLUSION: Our study reveals a protective effect of macrophage SR-A1-STAT3-IRG1 axis against aortic aneurysm formation via inhibiting inflammation.

SRA inhibition improves antitumor potency of antigen-targeted chaperone vaccine.

We have previously demonstrated that scavenger receptor A (SRA) acts as an immunosuppressive regulator of dendritic cell (DC) function in activating antitumor T cells. Here we investigate the potential of inhibiting SRA activity to enhance DC-targeted chaperone vaccines including one that was recently evaluated in melanoma patients. We show that short hairpin RNA-mediated SRA silencing significantly enhances the immunogenicity of DCs that have captured chaperone vaccines designed to target melanoma (i.e., hsp110-gp100) and breast cancer (i.e., hsp110-HER/Neu-ICD). SRA downregulation results in heightened activation of antigen-specific T cells and increased CD8+ T cell-dependent tumor inhibition. Additionally, small interfering RNA (siRNA) complexed with the biodegradable, biocompatible chitosan as a carrier can efficiently reduce SRA expression on CD11c+ DCs in vitro and in vivo. Our proof-of-concept study shows that direct administration of the chitosan-siRNA complex to mice promotes chaperone vaccine-elicited cytotoxic T lymphocyte (CTL) response, culminating in improved eradication of experimental melanoma metastases. Targeting SRA with this chitosan-siRNA regimen combined with the chaperone vaccine also leads to reprogramming of the tumor environment, indicated by elevation of the cytokine genes (i.e., ifng, il12) known to skew Th1-like cellular immunity and increased tumor infiltration by IFN-γ+CD8+ CTLs as well as IL-12+CD11c+ DCs. Given the promising antitumor activity and safety profile of chaperone vaccine in cancer patients, further optimization of the chitosan-siRNA formulation to potentially broaden the immunotherapeutic benefits of chaperone vaccine is warranted.

Prognostic and predictive significance of serum soluble scavenger receptor A in acute primary basal ganglia hemorrhage: A prospective cohort study.

BACKGROUND: Scavenger receptor A (SRA) can regulate immune response and is involved in pathophysiological processes of acute brain injury. We analyzed the prognostic role of serum soluble SRA in intracerebral hemorrhage (ICH). METHODS: In this prospective cohort study of 110 healthy controls and 110 patients with acute basal ganglia hemorrhage, serum soluble SRA concentrations were detected. Univariate analyses, followed by multivariate logistic regression analyses, were utilized to explore the relationship between serum soluble SRA concentrations and early neurologic deterioration (END) plus post-stroke 3-month poor prognosis (modified Rankin Scale scores of 3-6). RESULTS: Serum soluble SRA concentrations of patients were significantly higher than those of controls (median, 3.6 vs 0.9 ng/ml; P < 0.001). Serum soluble SRA concentrations of patients were independently correlated with hematoma volume (ß, 0.201; 95 % confidence interval (CI), 0.093-0.309; P = 0.001), National Institutes of Health Stroke Scale (NIHSS) scores (ß, 0.118; 95 % CI, 0.024-0.213; P = 0.024), and 3-month modified Rankin Scale scores (ß, 0.148; 95 % CI, 0.063-0.232; P = 0.001). Serum soluble SRA concentrations independently predicted END and poor 3-month prognosis with odds ratio values of 1.394 (95 % CI, 1.024-1.899; P = 0.035) and 1.441 (95 % CI, 1.016-2.044; P = 0.040) respectively. Serum soluble SRA concentrations were efficiently predictive of the development of END (ROC AUC 0.746; 95 % CI, 0.631-0.861) and poor 3-month prognosis (AUC, 0.773; 95 % CI, 0.685-0.861). Serum soluble SRA concentrations significantly improved AUCs of NIHSS score and hematoma volume to 0.889 (95 % CI, 0.829-0.948; P = 0.035) and 0.873 (95 % CI, 0.811-0.936; P = 0.036) for prognostic prediction. The END predictive ability of serum sSRA concentrations combined with NIHSS score and ICH volume (AUC, 0.900; 95 % CI, 0.835-0.965) was significantly superior to those of NIHSS score (P = 0.020) and hematoma volume (P = 0.022). The prognostic predictive capability of serum sSRA concentrations combined with NIHSS score and ICH volume (AUC, 0.907; 95 % CI, 0.852-0.962) substantially exceeded those of NIHSS score (P = 0.009) and hematoma volume (P = 0.005). CONCLUSIONS: Serum soluble SRA concentrations may reflect illness severity and neurologic function after ICH, indicating serum soluble SRA may serve as a promising prognostic biochemical marker of ICH.

SRA Suppresses Antiviral Innate Immune Response in Macrophages by Limiting TBK1 K63 Ubiquitination via Deubiquitinase USP15.

The innate immune system is the first line of host defense against microbial infections. During virus infection, pattern recognition receptors (PRRs) are engaged to detect specific viral components, such as viral RNA or DNA, and regulate the innate immune response in the infected cells or immune cells. Our previous study demonstrated that scavenger receptor A (SRA), an important innate PRR, impaired the anti-hepatitis B virus (HBV) response in hepatocytes. Given that SRA is primarily expressed in macrophages, here, we assessed the function of SRA expressed in macrophages in response to RNA or DNA viral infection. SRA-deficient (SRA-/-) mice showed reduced susceptibility to viral infection caused by vesicular stomatitis virus (VSV) or herpes simplex virus 1 (HSV-1). In the virus-infected SRA-/- mice, compared with their wild-type (WT) counterparts, we observed low amounts of virus accompanied by enhanced interferon (IFN) production. Furthermore, SRA significantly inhibited the phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). We provided biochemical evidence showing that SRA directly interacts with the N-terminal kinase domain (KD) of TBK1, resulting in the limitation of its K63-linked ubiquitination. Moreover, we demonstrated that SRA negatively regulates the activity of TBK1 by promoting the recruitment of ubiquitin-specific protease 15 (USP15) to deubiquitinate TBK1. In summary, we have identified the connection between SRA and the TBK1/IRF3 signaling pathway in macrophages, indicating a critical role of SRA in the regulation of host antiviral immunity. IMPORTANCE During virus infection, PRRs are engaged to detect specific viral components, such as viral RNA or DNA, and regulate the innate immune response in the infected cells or other immune cells. We reported that deficiency of SRA, an important innate PRR, promoted IRF3 activation, type I IFN production, and innate antiviral responses against RNA and DNA viruses in vivo and in vitro. Furthermore, the biochemical analysis showed that SRA directly interacts with the KD domain of TBK1 and limits its K63-linked polyubiquitination, reducing TBK1 activation. Further analyses determined that SRA is a modulator for TBK1 activation via the recruitment of USP15, which delineated a previously unrecognized function for SRA in innate antiviral immunity.

Serum Soluble Scavenger Receptor A Levels are Associated with Delayed Cerebral Ischemia and Poor Clinical Outcome After Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Study.

Objective: Scavenger receptor A (SRA), a pattern recognition molecule, is implicated in immune response after acute brain injury. We strived to identify serum soluble SRA (sSRA) as a potential biomarker of prognosis after aneurysmal subarachnoid hemorrhage (aSAH). Methods: In this prospective observational study, we quantified serum sSRA levels of 131 aSAH patients and 131 healthy controls. A poor outcome was defined as extended Glasgow outcome scale (GOSE) scores of 1-4 at 90 days after injury. Relations of serum sSRA levels to severity, delayed cerebral ischemia (DCI) and poor outcome were assessed using multivariate analysis. Predictive efficiency was determined via area under receiver operating characteristic curve (AUC). Results: Serum sSRA levels were markedly higher in aSAH patients than in controls (median, 2.9 ng/mL versus 1.0 ng/mL; P < 0.001). Serum sSRA levels were independently correlated with Hunt-Hess scores (beta, 0.569; 95% confidence interval (CI), 0.244-0.894; P = 0.001), modified Fisher scores (beta, 0.664; 95% CI, 0.254-1.074; P = 0.002) and 90-day GOSE scores (beta, -0.275; 95% CI, -0.440-0.110; P = 0.005). Serum sSRA levels independently predicted DCI (odds ratio, 1.305; 95% CI, 1.012-1.687; P = 0.040) and a poor outcome (odds ratio, 2.444; 95% CI, 1.264-4.726; P = 0.008), as well as showed significant accuracy for the discrimination of DCI (AUC, 0.753; 95% CI, 0.649-0.857; P < 0.001) and a poor outcome (AUC, 0.800; 95% CI, 0.721-0.880; P < 0.001). Its combination with Hunt-Hess scores and modified Fisher scores displayed significantly improved AUCs for predicting DCI and poor outcome, as compared to any of them (all P < 0.05). Conclusion: There is a significant elevation of serum sSRA levels after aSAH, which in close correlation with illness severity, are independently associated with DCI and poor clinical outcome after aSAH. Hypothetically, SRA may regulate immune response in acute brain injury after aSAH and serum sSRA is presumed to be a potential prognostic biomarker of aSAH.

Oxidised Low-Density Lipoprotein-Induced Platelet Hyperactivity-Receptors and Signalling Mechanisms.

Dyslipidaemia leads to proatherogenic oxidative lipid stress that promotes vascular inflammation and thrombosis, the pathologies that underpin myocardial infarction, stroke, and deep vein thrombosis. These prothrombotic states are driven, at least in part, by platelet hyperactivity, and they are concurrent with the appearancxe of oxidatively modified low-density lipoproteins (LDL) in the circulation. Modified LDL are heterogenous in nature but, in a general sense, constitute a prototype circulating transporter for a plethora of oxidised lipid epitopes that act as danger-associated molecular patterns. It is well-established that oxidatively modified LDL promote platelet activation and arterial thrombosis through a number of constitutively expressed scavenger receptors, which transduce atherogenic lipid stress to a complex array of proactivatory signalling pathways in the platelets. Stimulation of these signalling events underlie the ability of modified LDL to induce platelet activation and blunt platelet inhibitory pathways, as well as promote platelet-mediated coagulation. Accumulating evidence from patients at risk of arterial thrombosis and experimental animal models of disease suggest that oxidised LDL represents a tangible link between the dyslipidaemic environment and increased platelet activation. The aim of this review is to summarise recent advances in our understanding of the pro-thrombotic signalling events induced in platelets by modified LDL ligation, describe the contribution of individual platelet scavenger receptors, and highlight potential future challenges of targeting these pathways.

Scavenger receptor A in immunity and autoimmune diseases: Compelling evidence for targeted therapy.

INTRODUCTION: Scavenger receptor A (SR-A) is reported to be involved in innate and adaptive immunity and in recent years, the soluble form of SR-A has also been identified. Intriguingly, SR-A displays double-edged sword features in different diseases. Moreover, targeted therapy on SR-A, including genetic modulation, small molecule inhibitor, inhibitory peptides, fucoidan, and blocking antibodies, provides potential strategies for treatment. Currently, therapeutics targeting SR-A are in preclinical studies and clinical trials, revealing great perspectives in future immunotherapy. AREAS COVERED: Through searching PubMed (January 1979-March 2022) and clinicaltrials.gov, we review most of the research and clinical trials involving SR-A. This review briefly summarizes recent study advances on SR-A, with particular concern on its role in immunity and autoimmune diseases. EXPERT OPINION: Given the emerging evidence of SR-A in immunity, its targeted therapy has been studied in various diseases, especially autoimmune diseases. However, many challenges still remain to be overcome, such as the double-sworded effects and the specific isoform targeting. For further clinical success of SR-A targeted therapy, the crystal structure illustration and the dual function discrimination of SR-A should be further investigated. Nevertheless, although challenging, targeting SR-A would be a potential effective strategy in the treatment of autoimmune diseases and other immune-related diseases.

SR-A neutralizing antibody: potential drug candidate for ameliorating osteoclastogenesis in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by proliferative synovitis with deterioration of cartilage and bone. Osteoclasts (OCs) are the active participants in the bone destruction of RA. Although with great advances, most current therapeutic strategies for RA have limited effects on bone destruction. Macrophage scavenger receptor A (SR-A) is a class of pattern recognition receptors (PRRs) involved in bone metabolism and OC differentiation. More recently, our study revealed the critical role of SR-A in RA diagnosis and pathogenesis. Here, we further demonstrated that serum SR-A levels were positively correlated with bone destruction in patients with RA. Anti-SR-A neutralizing antibodies significantly inhibited OC differentiation and bone absorption in vitro in patients with RA, but not in healthy individuals, dampening the expression of OC-specific genes such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinase-9 (MMP-9). Similar results were also seen in collagen-induced arthritis (CIA) mice in vitro. Moreover, the anti-SR-A neutralizing antibody could further ameliorate osteoclastogenesis in vivo and ex vivo in CIA mice, accompanied by decreased serum levels of C-terminal telopeptide and IL-6, exhibiting potential protective effects. These results suggest that blockade of SR-A using anti-SR-A neutralizing antibodies might provide a promising therapeutic strategy for bone destruction in the RA.

Scavenger Receptor A1 Signaling Pathways Affecting Macrophage Functions in Innate and Adaptive Immunity.

First discovered on macrophages by Goldstein and Brown in 1979, Scavenger Receptors have since been shown to participate in a diverse number of cell functions; equally diverse are their structures and the ligands they bind. Macrophage activation is crucial in the outcome of an immune response. SR-A1 is highly abundant on macrophages and recognizes both host- and microorganism-derived molecules that impact processes that are initiated, perpetuated, or modified. This review summarizes the involvement of SR-A1 in both inflammatory and anti-inflammatory responses, the multiple-ligand internalization mechanisms and the diversity of signaling pathways that impact macrophage function and activation. Engagement of SR-A1 results in the stimulation of differential signaling pathways and patterns of cytokine expression, kinetics, magnitude of response and activation status. SR-A1 plays essential roles in phagocytosis and efferocytosis, interacting with other receptors and promoting tolerance in response to apoptotic cell uptake. In cell adhesion, tissue remodeling, and cell migration, SR-A1 signals through different pathways engaging different cytoplasmic motifs. We describe the role of SR-A1 during innate and adaptive immune responses, such as participation in macrophage polarization and interaction with other innate receptors, as well as in antigen uptake, processing, and presentation, regulating T and B cell activation. The dichotomous contribution of SR-A1 on macrophage functions is discussed. A better understanding of the role SR-A1 plays through molecular mechanisms and crosstalk with other receptors may provide insights into developing novel therapeutic strategies to modulate immune responses and immunopathologies.

L-theanine inhibits foam cell formation via promoting the scavenger receptor A degradation.

Atherosclerosis is one of the most common cardiovascular diseases with highly mortality worldwide. The formation of foam cell plays an important role in the early stage of atherosclerosis pathogenesis. L-theanine is the most abundant free amino acid in tea, which possesses anti-inflammatory, anti-tumor and anti-atherosclerosis effects. However, little is known about the effects of L-theanine on the foam cell formation. In our study, RAW264.7 cells and primary mouse peritoneal macrophages were exposed to oxidized low density lipoprotein (ox-LDL) for inducing foam cell formation. We found that L-theanine significantly impeded cholesterol accumulation in macrophages, while inhibiting the formation of foam cell. Our further experiments showed that L-theanine attenuated the cholesterol uptake of RAW264.7 cells and primary mouse peritoneal macrophages by reducing the protein level of macrophage scavenger receptor A (SR-A), but not the level of mRNA suggesting that L-theanine regulates scavenger receptor A at the translational rather than transcriptional level. The present results demonstrated that L-theanine obviously promoted the degradation of scavenger receptor A protein and scavenger receptor A was degraded by ubiquitination dependent manner. Collectively, our research indicates that L-theanine suppresses the formation of macrophage foam cell by promoting the ubiquitination dependent degradation of scavenger receptor A.

Scavenger receptor A1 participates in uptake of Leptospira interrogans serovar Autumnalis strain 56606v and inflammation in mouse macrophages.

Leptospirosis, caused by pathogenic Leptospira species, has emerged as a widespread zoonotic disease worldwide. Macrophages mediate the elimination of pathogens through phagocytosis and cytokine production. Scavenger receptor A1 (SR-A1), one of the critical receptors mediating this process, plays a complicated role in innate immunity. However, the role of SR-A1 in the immune response against pathogenic Leptospira invasion is unknown. In the present study, we found that SR-A1 is an important nonopsonic phagocytic receptor on murine macrophages for Leptospira. However, intraperitoneal injection of leptospires into WT mice presented with more apparent jaundice, subcutaneous hemorrhaging, and higher bacteria burdens in blood and tissues than that of SR-A1-/- mice. Exacerbated cytokine and inflammatory mediator levels were also observed in WT mice and higher recruited macrophages in the liver than those of SR-A1-/- mice. Our findings collectively reveal that although beneficial in the uptake of Leptospira by macrophage, SR-A1 might be exploited by Leptospira to modulate inflammatory activation and increase the susceptibility of infection in the host. These results provide our new insights into the innate immune response during early infection by L. interrogans.

Palmitic acid-modified bovine serum albumin nanoparticles target scavenger receptor-A on activated macrophages to treat rheumatoid arthritis.

Palmitic acid-modified bovine serum albumin (PAB) was synthetized and found to own remarkable scavenger receptor-A (SR-A) targeting ability in vitro and in vivo, through which activated macrophages took up PAB nanoparticles (PAB NPs) 9.10 times more than bovine serum albumin nanoparticles (BSA NPs) and PAB NPs could delivery anti-inflammatory drugs celastrol (CLT) to inflamed tissues more effectively than BSA NPs. Compared with chondroitin sulfate modified BSA NPs targeting activated macrophages via CD44, PAB NPs show a more prominent targeting effect whether in vivo or in vitro. And PAB also demonstrated excellent biosafety compared to maleylated BSA, a known SR-A ligand that was lethal in our study. Furthermore, in adjuvant-induced arthritis rats, CLT-PAB NPs significantly improved disease pathology at a lower CLT dose with high safety, compared with CLT-BSA NPs. In addition, compared with the existing ligands with SR-A targeting due to strong electronegativity, the enhanced electronegativity and introduced PA are both important for the SR-A targeting effect of PAB. Therefore, PAB provides a novel direction for the treatment of rheumatoid arthritis and design of new ligands of SR-A.

Application of a Scavenger Receptor A1-Targeted Polymeric Prodrug Platform for Lymphatic Drug Delivery in HIV.

We have developed a macromolecular prodrug platform based on poly(l-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with the SR-A inhibitor polyinosinic acid (poly I). Further, we observed no uptake of PLS in an SR-A1-deficient RAW 264.7 cell line, even after 24 h incubation. In mice, PLS distributed to lymphatic organs following i.v. injection, as observed by ex vivo fluorescent imaging, and accumulated in lymph nodes following both i.v. and i.d. administrations, based on immunohistochemical analysis with high-resolution microscopy. As a proof-of-concept, the HIV antiviral emtricitabine (FTC) was conjugated to the polymer's succinyl groups via ester bonds, with a drug loading of 14.2% (wt/wt). The prodrug (PLS-FTC) demonstrated controlled release properties in vitro with a release half-life of 15 h in human plasma and 29 h in esterase-inhibited plasma, indicating that drug release occurs through both enzymatic and nonenzymatic mechanisms. Upon incubation of PLS-FTC with human peripheral blood mononuclear cells (PBMCs), the released drug was converted to the active metabolite FTC triphosphate. In a pharmacokinetic study in rats, the prodrug achieved ∼7-19-fold higher concentrations in lymphatic tissues compared to those in FTC control, supporting lymphatic-targeted drug delivery. We believe that the SR-A1-targeted macromolecular PLS prodrug platform has extraordinary potential for the treatment of infectious diseases.