Requirement of scavenger receptors for activation of the IRF-3/IFN-ß/STAT-1 pathway in TLR4-mediated production of NO by LPS-activated macrophages.

Production of nitric oxide (NO) by LPS-activated macrophages is due to a complex cellular signaling initiated by TLR4 that leads to the transcription of IFN-ß, which activates IRF-1 and STAT-1, as well as to the activation of NF-κB, required for iNOS transcription. High concentrations of LPS can also be uptaken by scavenger receptors (SRs), which, in concert with TLR4, leads to inflammatory responses. The mechanisms by which TLR4 and SRs interact, and the pathways activated by this interaction in macrophages are not elucidated. Therefore, our main goal was to evaluate the role of SRs, particularly SR-A, in LPS-stimulated macrophages for NO production. We first showed that, surprisingly, LPS can induce the expression of iNOS and the production of NO in TLR4-/- mice, provided exogenous IFN-ß is supplied. These results indicate that LPS stimulate receptors other than TLR4. The inhibition of SR-A using DSS or neutralizing antibody to SR-AI showed that SR-A is essential for the expression of iNOS and NO production in stimulation of TLR4 by LPS. The restoration of the ability to express iNOS and produce NO by addition of rIFN-ß to inhibited SR-A cells indicated that the role of SR-AI in LPS-induced NO production is to provide IFN-ß, probably by mediating the internalization of LPS/TLR4, and the differential inhibition by DSS and neutralizing antibody to SR-AI suggested that other SRs are also involved. Our results reinforce that TLR4 and SR-A act in concert in LPS activation and demonstrated that, for the production of NO, it does mainly by synthesizing IRF-3 and also by activating the TRIF/IRF-3 pathway for IFN-ß production, essential for LPS-mediated transcription of iNOS. Consequently STAT-1 is activated, and IRF-1 is expressed, which together with NF-κB from TLR4/MyD88/TIRAP, induce iNOS synthesis and NO production. SUMMARY SENTENCE: TLR4 and SRs act in concert activating IRF-3 to transcribe IFN-ß and activate STAT-1 to produce NO by LPS-activated macrophages.

Scavenger Receptors in the Pathogenesis of Viral Infections.

Scavenger receptors (SR) are not only pattern recognition receptors involved in the immune response against pathogens but are also important receptors exploited by different virus to enter host cells, and thus represent targets for antiviral therapy. The high mutation rates of viruses, as well as their small genomes are partly responsible for the high rates of virus resistance and effective treatments remain a challenge. Most currently approved formulations target viral-encoded factors. Nevertheless, host proteins may function as additional targets. Thus, there is a need to explore and develop new strategies aiming at cellular factors involved in virus replication and host cell entry. SR-virus interactions have implications in the pathogenesis of several viral diseases and in adenovirus-based vaccination and gene transfer technologies, and may function as markers of severe progression. Inhibition of SR could reduce adenoviral uptake and improve gene therapy and vaccination, as well as reduce pathogenesis. In this review, we will examine the crucial role of SR play in cell entry of different types of human virus, which will allow us to further understand their role in protection and pathogenesis and its potential as antiviral molecules. The recent discovery of SR-B1 as co-factor of SARS-Cov-2 (severe acute respiratory syndrome coronavirus 2) entry is also discussed. Further fundamental research is essential to understand molecular interactions in the dynamic virus-host cell interplay through SR for rational design of therapeutic strategies.

Molecular characterization and functional analysis of scavenger receptor class B from black tiger shrimp (Penaeus monodon)

BACKGROUND: Scavenger receptor class B (SRB) is a multifunctional protein in animals that participates in physiological processes, including recognition of a wide range of ligands. Astaxanthin is a major carotenoid found in shrimp. However, the molecular mechanism of astaxanthin and SRB protein binding has not been reported. RESULTS: In the present study, a member of the SRB subfamily, named PmSRB, was identified from the transcriptome of black tiger shrimp (Penaeus monodon). The open reading frame of PmSRB was 1557 bp in length and encoded 518 amino acids. The structure of PmSRB included a putative transmembrane structure at the N-terminal region and a CD36 domain. Multiple sequence alignment indicated that the CD36 domain were conserved. Phylogenetic analysis showed four separate branches (SRA, SRB, SRC, and croquemort) in the phylogenetic tree and that PmSRB was clustered with SRB of Eriocheir sinensis. Quantitative real-time polymerase chain reaction showed that the PmSRB gene was widely expressed in all tissues tested, with the highest expression level observed in the lymphoid organ and brain. Subcellular localization analysis revealed that PmSRB-GFP (green fluorescent protein) fusion proteins were predominantly localized in the cell membrane. The recombinant proteins of PmSRB showed binding activities against astaxanthin in vitro. CONCLUSIONS: PmSRB was identified and characterized in this study. It is firstly reported that PmSRB may take as an important mediator of astaxanthin uptake in shrimp.

B cells interactions in lipid immune responses: implications in atherosclerotic disease.

Atherosclerosis is considered as an inflammatory and chronic disorder with an important immunologic component, which underlies the majority of cardiovascular diseases; condition that belongs to a group of noncommunicable diseases that to date and despite of prevention and treatment approaches, they remain as the main cause of death worldwide, with 17.5 million of deaths every year. The impact of lipids in human health and disease is taking center stage in research, due to lipotoxicity explained by elevated concentration of circulating lipids, in addition to altered adipose tissue metabolism, and aberrant intracellular signaling. Immune response and metabolic regulation are highly integrated systems and the proper function of each one is dependent on the other. B lymphocytes express a variety of receptors that can recognize foreign, endogenous or modified self-antigens, among them oxidized low density lipoproteins, which are the main antigens in atherosclerosis. Mechanisms of B cells to recognize, remove and present lipids are not completely clear. However, it has been reported that B cell can recognize/remove lipids through a range of receptors, such as LDLR, CD1d, FcR and SR, which might have an atheroprotector or proatherogenic role during the course of atherosclerotic disease. Pertinent literature related to these receptors was examined to inform the present conclusions.

Expression Pattern of Scavenger Receptors and Amyloid-ß Phagocytosis of Astrocytes and Microglia in Culture are Modified by Acidosis: Implications for Alzheimer's Disease.

The pathological hallmarks of Alzheimer's disease (AD) are amyloid-ß (Aß) plaques, neurofibrillary tangles, and glia activation. The pathology also includes vascular amyloidosis and cerebrovascular disease. Vascular compromise can result in hypoperfusion, local tissue hypoxia, and acidosis. Activated microglia and astrocytes can phagocytose Aß through membrane receptors that include scavenger receptors. Changes in glial cells induced by extracellular acidosis could play a role in the development of AD. Here, we assess whether extracellular acidosis changes glial cell properties relevant for Aß clearance capacity. Incubation of glial cells on acidified culture medium (pH 6.9 or 6.5) for 24-48 h resulted in decreased cell diameter, with thinner branches in astrocytes, slight reduction in cell body size in microglia, a transient decrease in astrocyte adhesion to substrates, and a persistent decrease in microglia adhesion compared with control media (pH 7.4). Astrocyte Aß phagocytosis decreased at pH 6.9 and 6.5, whereas microglia phagocytosis only transiently decreased in acidified media. Scavenger receptors class B member I (SR-BI) increased and scavenger receptors-macrophage receptors with collagenous structures (SR-MARCO) decreased in astrocytes cultured at pH 6.5. In contrast, in microglia exposed to pH 6.5, expression of SR-BI and SR-MARCO increased and fatty acid translocase (CD-36) decreased. In conclusion, the acidic environment changed the adhesiveness and morphology of both microglia and astrocytes, but only astrocytes showed a persistent decrease in Aß clearance activity. Expression of scavenger receptors was affected differentially in microglia and astrocytes by acidosis. These changes in scavenger receptor patterns can affect the activation of glia and their contribution to neurodegeneration.