The Antimicrobial Peptide Cathelicidin Exerts Immunomodulatory Effects via Scavenger Receptors.

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents.

CD163L1+CXCL10+ Macrophages are Enriched Within Colonic Lamina Propria of Diverticulitis Patients.

BACKGROUND: Inflammation of diverticula, which are outpouchings of the colonic bowl wall, causes diverticulitis. Severe cases of diverticulitis require surgical intervention. Through RNA-seq analysis of intestinal tissues, we previously found that the innate immune response was deregulated in surgical diverticulitis patients. In that study, pro-inflammatory and macrophage markers were differentially expressed in the colons of diverticulitis versus control patients. Here we investigate CD163L1+ macrophages and the pro-inflammatory chemokine, CXCL10, in diverticulitis. MATERIALS AND METHODS: We assessed tissue from an uninvolved area adjacent to a region of the sigmoid colon chronically affected by diverticulitis and performed Spearman's correlation on transcripts associated with macrophage signaling. We identified altered CD163L1 and CXCL10 gene expression levels that we confirmed by RT-qPCR analysis on an independent cohort of diverticulitis patients and controls. We used immunofluorescence microscopy to localize CD163L1+ macrophages and CXCL10 levels in intestinal tissue and ELISA to measure CXCL10 levels in patient serum. RESULTS: We found a positive correlation between intestinal CD163L1 and CXCL10 gene expression and an increased number of CD163L1+ macrophages in the sigmoid colons of diverticulitis patients relative to controls (P = 0.036). Macrophages at the apices of colonic crypts expressed the chemokine CXCL10. Correspondingly, these diverticulitis patients also displayed heightened CXCL10 levels in their serum (P = 0.007). CONCLUSIONS: We identified a novel population of CD163L1+CXCL10+ macrophages in the colonic crypts of diverticulitis patients and demonstrated increased expression of serum CXCL10 in these patients. CXCL10 may serve as a prognostic biomarker to aid in clinical decision making for diverticulitis patients.

The Role of Renal Macrophage, AIM, and TGF-ß1 Expression in Renal Fibrosis Progression in IgAN Patients.

Objective: To analyze the expression of macrophages, AIM, TGF-ß1 in the kidney of IgAN patients, and to explore the role of macrophages, AIM, TGF-ß1 in the progression of renal fibrosis in IgAN patients. Methods: The paraffin specimens of renal tissue from 40 IgAN patients were selected as the observation group. At the same time, paraffin specimens of normal renal tissue from 11 patients treated by nephrectomy were selected as the normal control group. We observed the distribution of macrophages, the expression of AIM and TGF-ß1 by immunohistochemical staining and/or immunofluorescence. Result: The number of M0, M1, M2 macrophages could be found increased in IgAN patients. M0 macrophages are mainly polarized towards M2 macrophages. The expression of AIM and TGF-ß1 were significantly higher in IgAN patients than in NC. M2 macrophage, AIM and TGF-ß1 were positively correlated with serum creatinine and 24-hour proteinuria, but negatively correlated with eGFR. M2 macrophages, AIM, TGF-ß1 were positively correlated with fibrotic area. Conclusion: M2 macrophages, AIM and TGF-ß1 play important roles in the process of IgAN fibrosis, and the three influence each other.

IL-23p19 and CD5 antigen-like form a possible novel heterodimeric cytokine and contribute to experimental autoimmune encephalomyelitis development.

Among various cytokines, interleukin (IL)-12 family cytokines have very unique characteristics in that they are composed of two distinct subunits and these subunits are shared with each other. IL-23, one of the IL-12 family cytokines, consists of p19 and p40 subunits, is mainly produced by antigen-presenting cells, and plays a critical role in the expansion and maintenance of pathogenic helper CD4+ T (Th)17 cells. Since we initially found that p19 is secreted in the culture supernatant of activated CD4+ T cells, we have further investigated the role of p19. p19 was revealed to associate with CD5 antigen-like (CD5L), which is a repressor of Th17 pathogenicity and is highly expressed in non-pathogenic Th17 cells, to form a composite p19/CD5L. This p19/CD5L was shown to activate STAT5 and enhance the differentiation into granulocyte macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells. Both CD4+ T cell-specific conditional p19-deficient mice and complete CD5L-deficient mice showed significantly alleviated experimental autoimmune encephalomyelitis (EAE) with reduced frequency of GM-CSF+CD4+ T cells. During the course of EAE, the serum level of p19/CD5L, but not CD5L, correlated highly with the clinical symptoms. Thus, the composite p19/CD5L is a possible novel heterodimeric cytokine that contributes to EAE development with GM-CSF up-regulation.

The neurorepellent, Slit2, prevents macrophage lipid loading by inhibiting CD36-dependent binding and internalization of oxidized low-density lipoprotein.

Atherosclerosis is characterized by retention of modified lipoproteins, especially oxidized low density lipoprotein (oxLDL) within the sub-endothelial space of affected blood vessels. Recruited monocyte-derived and tissue-resident macrophages subsequently ingest oxLDL by binding and internalizing oxLDL via scavenger receptors, particularly CD36. The secreted neurorepellent, Slit2, acting through its transmembrane receptor, Roundabout-1 (Robo-1), was previously shown to inhibit recruitment of monocytes into nascent atherosclerotic lesions. The effects of Slit2 on oxLDL uptake by macrophages have not been explored. We report here that Slit2 inhibits uptake of oxLDL by human and murine macrophages, and the resulting formation of foam cells, in a Rac1-dependent and CD36-dependent manner. Exposure of macrophages to Slit2 prevented binding of oxLDL to the surface of cells. Using super-resolution microscopy, we observed that exposure of macrophages to Slit2 induced profound cytoskeletal remodeling with formation of a thick ring of cortical actin within which clusters of CD36 could not aggregate, thereby attenuating binding of oxLDL to the surface of cells. By inhibiting recruitment of monocytes into early atherosclerotic lesions, and the subsequent binding and internalization of oxLDL by macrophages, Slit2 could represent a potent new tool to combat individual steps that collectively result in progression of atherosclerosis.

Apoptosis inhibitor of macrophage (AIM) contributes to IL-10-induced anti-inflammatory response through inhibition of inflammasome activation.

Apoptosis inhibitor of macrophage (AIM) modulates the signaling in inflammatory responses, including infection, cancer, or other immune diseases. Recent studies suggest that like interleukin-10 (IL-10), AIM is involved in alternatively activated (M2) macrophage polarization. We aimed to understand whether and how AIM is involved in IL-10-induced inhibition of inflammasome activation and resolution of inflammation. First, we demonstrated that IL-10 induced increases in mRNA and protein expression of AIM in murine bone marrow-derived macrophages (BMDM). In addition, genetic and pharmacologic inhibition of STAT3 (signal transducer and activator of transcription 3) reduced IL-10-induced AIM expression. We also found that IL-10-induced STAT3 activity enhanced the AIM promoter activity by directly binding the promoter of the AIM gene. Additionally, reduction of LPS/adenosine triphosphate (ATP)-induced IL-1ß production and caspase-1 activation by IL-10 was reversed in BMDM from AIM-/- mice. Treatment of BMDM from both wild type (WT) and IL-10-/- mice with recombinant AIM showed the inhibitory effects on IL-1ß and IL-18 production and caspase-1 activation. Endogenous and exogenous AIM inhibited apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) speck formation. In LPS-induced acute peritonitis, inhibition of IL-1ß and IL-18 production in peritoneal lavage fluid (PLF) and serum, reduction of caspase-1 activation in peritoneal macrophages, and reduction of numbers of neutrophils and peritoneal macrophages in PLF by administration of IL-10 were not evident in AIM-/- mice. Our in vitro and in vivo data reveal a novel role of AIM in the inhibition of inflammasome-mediated caspase-1 activation and IL-1ß and IL-18 production.

Scavenger receptor B8 improves survivability by mediating innate immunity in silkworm, Bombyx mori.

Scavenger receptor class B (SR-B) is an extracellular transmembrane glycoprotein that plays a vital role in innate immunity. Although SR-Bs have been widely studied in vertebrates, their functions remained to elucidate in insects. Here, we identified and characterized a scavenger receptor class B member from the silkworm, Bombyx mori (designated as BmSCRB8). BmSCRB8 is broadly expressed in various immune tissues/organs, including fat body, gut, and hemocyte. Its expression is dramatically enhanced after challenge with different types of bacteria or pathogen-associated molecular patterns (PAMPs). The recombinant BmSCRB8 protein can detect different types of bacteria by directly binding to PAMPs and significantly improve the bacterial clearance in vivo. After knockdown of BmSCRB8, the pathogenic bacterial clearance was strongly impaired, and several AMP genes were down-regulated following E. coli challenge. Moreover, pathogenic bacteria's treatment following the depletion of BmSCRB8 remarkably decreased silkworm larvae's survival rate. Taken together, these results demonstrate that BmSCRB8 acts as a pattern recognition protein and plays an essential role in silkworm innate immunity by enhancing bacterial clearance and contributing to the production of AMPs in vivo.

Soluble CD5 and CD6: Lymphocytic Class I Scavenger Receptors as Immunotherapeutic Agents.

CD5 and CD6 are closely related signal-transducing class I scavenger receptors mainly expressed on lymphocytes. Both receptors are involved in the modulation of the activation and differentiation cell processes triggered by clonotypic antigen-specific receptors present on T and B cells (TCR and BCR, respectively). To serve such a relevant immunomodulatory function, the extracellular region of CD5 and CD6 interacts with soluble and/or cell-bound endogenous counterreceptors but also microbial-associated molecular patterns (MAMPs). Evidence from genetically-modified mouse models indicates that the absence or blockade of CD5- and CD6-mediated signals results in dysregulated immune responses, which may be deleterious or advantageous in some pathological conditions, such as infection, cancer or autoimmunity. Bench to bedside translation from transgenic data is constrained by ethical concerns which can be overcome by exogenous administration of soluble proteins acting as decoy receptors and leading to transient "functional knockdown". This review gathers information currently available on the therapeutic efficacy of soluble CD5 and CD6 receptor infusion in different experimental models of disease. The existing proof-of-concept warrants the interest of soluble CD5 and CD6 as safe and efficient immunotherapeutic agents in diverse and relevant pathological conditions.

Macrophages and scavenger receptors in obesity-associated non-alcoholic liver fatty disease (NAFLD).

With an increase in sedentary lifestyle and dietary over nutrition, obesity has become one of the major public health problems worldwide and is a prevalent predisposing risk factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western developed countries. NAFLD represents a series of diseased states ranging from non-alcoholic fatty liver (NAFL) to steatohepatitis (NASH), which can lead to fibrosis and eventually to cirrhosis and hepatocellular carcinoma. Currently, the only effective treatment to cure end-stage liver disease is liver transplantation. Macrophages have been reported to play a crucial role in the progression of NAFLD, thereby are a potential target for therapy. In this review, we discuss the current knowledge on the role of macrophages and inflammatory signalling pathways associated with obesity and chronic liver inflammation, and their contribution to NAFLD development and progression.

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Development of an Enterovirus 71 Vaccine Efficacy Test Using Human Scavenger Receptor B2 Transgenic Mice.

Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease, and it sometimes causes severe neurological disease. Development of effective vaccines and animal models to evaluate vaccine candidates are needed. However, the animal models currently used for vaccine efficacy testing, monkeys and neonatal mice, have economic, ethical, and practical drawbacks. In addition, EV71 strains prepared for lethal challenge often develop decreased virulence during propagation in cell culture. To overcome these problems, we used a mouse model expressing human scavenger receptor B2 (hSCARB2) that showed lifelong susceptibility to EV71. We selected virulent EV71 strains belonging to the subgenogroups B4, B5, C1, C2, and C4 and propagated them using a culture method for EV71 without an apparent reduction in virulence. Here, we describe a novel EV71 vaccine efficacy test based on these hSCARB2 transgenic (Tg) mice and these virulent viruses. Adult Tg mice were immunized subcutaneously with formalin-inactivated EV71. The vaccine elicited sufficient levels of neutralizing antibodies in the immunized mice. The mice were subjected to lethal challenge with virulent viruses via intravenous injection. Survival, clinical signs, and body weight changes were observed for 2 weeks. Most immunized mice survived without clinical signs or histopathological lesions. The viral replication in immunized mice was much lower than that in nonimmunized mice. Mice immunized with the EV71 vaccine were only partially protected against lethal challenge with coxsackievirus A16. These results indicate that this new model is useful for in vivo EV71 vaccine efficacy testing.IMPORTANCE The development of new vaccines for EV71 relies on the availability of small animal models suitable for in vivo efficacy testing. Monkeys and neonatal mice have been used, but the use of these animals has several drawbacks, including high costs, limited susceptibility, and poor experimental reproducibility. In addition, the related ethical issues are considerable. The new efficacy test based on hSCARB2 Tg mice and virulent EV71 strains propagated in genetically modified cell lines presented here can overcome these disadvantages and is expected to accelerate the development of new EV71 vaccines.

Transcriptomic Analysis and High-dimensional Phenotypic Mapping of Mononuclear Phagocytes in Mesenteric Lymph Nodes Reveal Differences Between Ulcerative Colitis and Crohn's Disease.

BACKGROUND AND AIMS: Crohn's disease [CD] and ulcerative colitis [UC] are distinct forms of inflammatory bowel disease. Heterogeneity of HLA-DR+SIRPα + mononuclear phagocytes [MNPs], including macrophages [MΦ], monocyte-derived [Mono] cells, and dendritic cells [DCs], was reported in gut tissue but not yet investigated in mesenteric lymph nodes [MLNs] of IBD patients. We here compared the phenotype, function, and molecular profile of HLA-DR+SIRPα + MNPs in CD and UC MLNs. METHODS: Cell distribution, morphology, immune function, and transcriptomic [bulk RNAseq] and high-dimensional protein expression profiles [CyTOF] of HLA-DR+SIRPα + MNPs were examined in MLNs of UC [n = 14], CD [n = 35], and non-IBD [n = 12] patients. RESULTS: Elevated frequencies of CD14+CD64+CD163+ [Mono/MΦ-like] MNPs displaying monocyte/MΦ morphology and phagocytic function were a distinct feature of UC MLNs. In CD, the proportion of CD14-CD64-CD163- [DC-like] cells was augmented relative to Mono/MΦ-like cells; DC-like cells drove naïve T cell proliferation, Th1 polarisation, and Th17 TCM plasticity. Gene expression profile corroborated the nature of DC-like cells, best represented by BTLA, SERPINF, IGJ and, of Mono/MΦ-like cells, defined by CD163, MARCO, MAFB, CD300E, S100A9 expression. CyTOF analysis showed that CD123+ plasmacytoid cells predominated over conventional DCs in DC-like cells. Four CD163+ clusters were revealed in Mono/MΦ-like cells, two of which were enriched in MARCO-CD68dimHLA-DRdim monocyte-like cells and MARCOhiCD68hiHLA-DRhi Mɸ, whose proportion increased in UC relative to CD. CONCLUSIONS: Defining the landscape of MNPs in MLNs provided evidence for expansion of CD163+ Mono/MΦ-like cells in UC only, highlighting a distinction between UC and CD, and thus the potential contribution of monocyte-like cells in driving colitis.

SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties.

Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious and immunomodulatory agents. SP-A and SP-D bind numerous viruses including influenza A virus, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV), enhancing their clearance from mucosal points of entry and modulating the inflammatory response. They also have diverse roles in mediating innate and adaptive cell functions and in clearing apoptotic cells, allergens and other noxious particles. Here, we review how the properties of these first line defense molecules modulate inflammatory responses, as well as host-mediated immunopathology in response to viral infections. Since SP-A and SP-D are known to offer protection from viral and other infections, if their levels are decreased in some disease states as they are in severe asthma and chronic obstructive pulmonary disease (COPD), this may confer an increased risk of viral infection and exacerbations of disease. Recombinant molecules of SP-A and SP-D could be useful in both blocking respiratory viral infection while also modulating the immune system to prevent excessive inflammatory responses seen in, for example, RSV or coronavirus disease 2019 (COVID-19). Recombinant SP-A and SP-D could have therapeutic potential in neutralizing both current and future strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as well as modulating the inflammation-mediated pathology associated with COVID-19. A recombinant fragment of human (rfh)SP-D has recently been shown to neutralize SARS-CoV-2. Further work investigating the potential therapeutic role of SP-A and SP-D in COVID-19 and other infectious and inflammatory diseases is indicated.

Scavenger receptor class B type I (SR-BI) in Ruditapes philippinarum: A versatile receptor with multiple functions.

In the present study, a scavenger receptor class B type I (designed as RpSR-BI) was cloned and characterized from manila clam Ruditapes philippinarum. The full-length cDNA of RpSR-BI was of 2000 bp, containing an open reading frame (ORF) of 1515 bp. Multiple alignments and phylogenetic analysis strongly suggested that RpSR-BI was a member of the scavenger receptors family. The mRNA transcript of RpSR-BI was constitutively expressed in all tested tissues, and mainly expressed in hepatopancreas and hemocytes. Generally, Vibrio anguillarum or Micrococcus luteus challenge induced the expression of RpSR-BI transcripts in hemocytes of manila clams. Recombinant protein of RpSR-BI (rRpSR-BI) could bind lipopolysaccharides, peptidoglycan and glucan, but not chitin in vitro. Coinciding with the PAMPs binding assay, a broad agglutination spectrum was displayed by rRpSR-BI including Gram-positive bacteria and Gram-negative bacteria. Moreover, rRpSR-BI could enhance the phagocytosis and chemotaxis of hemocytes. These results showed that RpSR-BI functioned as a pattern recognition receptor (PRR) with distinct recognition spectrum, and also as an opsonin involved in the innate immune response of R. philippinarum.

Immunological Outcomes Mediated Upon Binding of Heat Shock Proteins to Scavenger Receptors SCARF1 and LOX-1, and Endocytosis by Mononuclear Phagocytes.

Heat shock proteins (HSP) are a highly abundant class of molecular chaperones that can be released into the extracellular milieu and influence the immune response. HSP release can occur when cells undergo necrosis and exude their contents. However, HSPs are also secreted from intact cells, either in free form or in lipid vesicles including exosomes to react with receptors on adjacent cells. Target cells are able recognize extracellular HSPs through cell surface receptors. These include scavenger receptors (SR) such as class E member oxidized low-density lipoprotein receptor-1 (LOX-1, aka OLR1, Clec8A, and SR-E1) and scavenger receptor class F member 1 (SCARF1, aka SREC1). Both receptors are expressed by dendritic cells (DC) and macrophages. These receptors can bind HSPs coupled to client binding proteins and deliver the chaperone substrate to the pathways of antigen processing in cells. SR are able to facilitate the delivery of client proteins to the proteasome, leading to antigen processing and presentation, and stimulation of adaptive immunity. HSPs may also may be involved in innate immunity through activation of inflammatory signaling pathways in a mechanism dependent on SR and toll-like receptor 4 (TLR4) on DC and macrophages. We will discuss the pathways by which HSPs can facilitate uptake of protein antigens and the receptors that regulate the ensuing immune response.

Scavenger Receptors: Promiscuous Players during Microbial Pathogenesis.

Innate immunity is the most broadly effective host defense, being essential to clear the majority of microbial infections. Scavenger Receptors comprise a family of sensors expressed in a multitude of host cells, whose dual role during microbial pathogenesis gained importance over recent years. SRs regulate the recruitment of immune cells and control both host inflammatory response and bacterial load. In turn, pathogens have evolved different strategies to overcome immune response, avoid recognition by SRs and exploit them to favor infection. Here, we discuss the most relevant findings regarding the interplay between SRs and pathogens, discussing how these multifunctional proteins recognize a panoply of ligands and act as bacterial phagocytic receptors.

The class D scavenger receptor CD68 contributes to mouse chronic liver injury.

Scavenger receptors, which are expressed on monocyte/macrophages, play a central role in many pathogenic processes. Here, we examined the role of the class D scavenger receptor (CD68) in bone marrow-derived monocyte/macrophages (BMMs) in chronic liver injury. The expression pattern of multiple scavenger receptors in two liver injury models (methionine-choline-deficient and high fat (MCDHF), carbon tetrachloride (CCl4)) were analyzed by qRT-PCR. CD68 expression was characterized by flow cytometric analysis, immunofluorescence, and qRT-PCR. A selective monocyte/macrophage toxicant, gadolinium chloride (GdCl3) was applied to analyze the function of CD68 in vitro and in vivo. Among the seven examined scavenger receptors (CD68, CD36, CD204, MARCO, LOX1, SREC, and CD163), the mRNA expression of CD68 first got uppermost and continuously increased throughout the entire stage of chronic liver injury, thus attracting our attention. In the injured liver, the percentage of recruited CD68+ BMM increased notably, aligning along the developing fibrotic septa, while the proportion of CD68+ KC stayed the same compared with that of control mice. In vitro CD68 was highly expressed in primary cultured BMM, and CD68 reduction was triggered by macrophage phagocytosis and apoptosis in the presence of GdCl3. In the damaged liver, the recruitment of CD68+ BMM and CD68 mRNA expression were reduced by GdCl3 administration, leading to the attenuation of liver inflammation and fibrosis. Altogether, scavenger receptor CD68 plays a key role in mouse chronic liver injury, which has important implications for the design of anti-fibrotic therapies.

Prokaryotic expression and identification of scavenger receptor B2.

There is still no effective clinical antiviral drug against human enterovirus 71 (EV71) infection, which causes hand, foot and mouth disease (HFMD) in children. Scavenger receptor class B member 2 (SCARB2) is an important receptor of EV71 as it plays a vital role in the early steps of viral infection. In this study, recombinant SCARB2 protein was expressed and purified in a prokaryotic expression system, and was identified by western blot with a monoclonal antibody and mass spectrometry analysis. Detection of the sera from mice immunized with the recombinant SCARB2 protein using ELISA and western blot showed good immunogenicity of the recombinant protein. Furthermore, in the neutralization test cytopathic effect was significantly decreased when EV71 was incubated with the immune sera before infection. In summary, the SCARB2 protein was expressed successfully, and the immune sera showed obvious antiviral effect against EV71. This study provides useful information about the interaction mechanism between SCARB2 and EV71, and is also helpful for further clinical treatment research of HFMD.

Role of a macrophage receptor with collagenous structure (MARCO) in regulating monocyte/macrophage functions in ayu, Plecoglossus altivelis.

Macrophage receptor with collagenous structure (MARCO) plays essential roles in phagocytic cell-mediated innate immune responses. However, studies regarding MARCO, especially its functions, are limited in teleost species. In this study, we identified a MARCO molecule (PaMARCO) from ayu (Plecoglossus altivelis). PaMARCO shared conserved functional domains with its mammalian counterparts. Sequence analysis showed that PaMARCO was most closely related to its rainbow trout (Oncorhynchus mykiss) counterpart. PaMARCO expression was upregulated in all tested immune tissues and monocytes/macrophages (MO/MΦ) upon Vibrio anguillarum infection, and blocking its function significantly decreased the immune responses of MO/MΦ during infection. PaMARCO could bind to the tested gram-positive and -negative bacteria in a Ca2+-dependent manner in vitro. Furthermore, the phagocytosis and bacterial killing activities of MO/MΦ were significantly decreased upon PaMARCO blockade using anti-PaMARCO IgG. PaMARCO was also involved in the polarization processes of ayu MO/MΦ. The upregulated expression of representative cytokines in LPS-induced M1 type (TNF-α, IL-1ß) or cAMP-induced M2 type (TGF-ß, IL-10) were inhibited in the anti-PaMARCO IgG-treated group, indicating that PaMARCO may be involved in the regulation of both inflammation priming and inflammation resolution of MO/MΦ. In conclusion, our results implicate that PaMARCO has essential regulatory roles for bacterial binding, clearance, and the polarization processes of ayu MO/MΦ.

More Than Just a Removal Service: Scavenger Receptors in Leukocyte Trafficking.

Scavenger receptors are a highly diverse superfamily of proteins which are grouped by their inherent ability to bind and internalize a wide array of structurally diverse ligands which can be either endogenous or exogenous in nature. Consequently, scavenger receptors are known to play important roles in host homeostasis, with common endogenous ligands including apoptotic cells, and modified low density lipoproteins (LDLs); additionally, scavenger receptors are key regulators of inflammatory diseases, such as atherosclerosis. Also, as a consequence of their affinity for a wide range of microbial products, their role in innate immunity is also being increasingly studied. However, in this review, a secondary function of a number of endothelial-expressed scavenger receptors is discussed. There is increasing evidence that some endothelial-expressed scavenger receptors are able to directly bind leukocyte-expressed ligands and subsequently act as adhesion molecules in the trafficking of leukocytes in lymphatic and vascular tissues. Here, we cover the current literature on this alternative role for endothelial-expressed scavenger receptors and also speculate on their therapeutic potential.