Macrophage scavenger receptor MARCO: In vitro and in vivo regulation and involvement in the anti-bacterial host defense

Apoptosis of cells must be regulated both positively and negatively in response to a variety of stimuli in the body. Various environmental stresses are known to initiate apoptosis via differential signal transduction cascades. However, induction of signals that may inhibit apoptosis is poorly understood, although a number of intracellular molecules that mediate inhibition of apoptosis have been identified. Here we present a novel murine macrophage-specific 54-kD secreted protein which inhibits apoptosis (termed AIM, for apoptosis inhibitor expressed by macrophages). AIM belongs to the macrophage scavenger receptor cysteine-rich domain superfamily (SRCR-SF), members of which share a highly homologous conserved cysteine-rich domain. In AIM-deficient mice, the thymocyte numbers were diminished to half those in wild-type mice, and CD4/CD8 double-positive (DP) thymocytes were strikingly more susceptible to apoptosis induced by both dexamethasone and irradiation in vivo. Recombinant AIM protein significantly inhibited cell death of DP thymocytes in response to a variety of stimuli in vitro. These results indicate that in the thymus, AIM functions in trans to induce resistance to apoptosis within DP cells, and thus supports the viability of DP thymocytes before thymic selection.

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Discrepancies in the in vitro and in vivo role of scavenger receptors in clearance of nanoparticles by Kupffer cells

Precision Nanomedicine ◽

10.29016/180430.1 ◽

2018 ◽

Vol 1 (1) ◽

pp. 76-84 ◽

Cited By ~ 3

Author(s):

Guankui Wang ◽

Ernest Groman ◽

Dmitri Simberg

Keyword(s):

Kupffer Cells ◽

Half Life ◽

Scavenger Receptor ◽

Superparamagnetic Iron Oxide ◽

Macrophage Scavenger Receptor ◽

Polyinosinic Acid ◽

Efficient Uptake

Nanoparticles are recognized and cleared by Kupffer cells (KCs) in the liver. This process complicates the development of targeted nanoparticles because of significant reduction of number of nanoparticles that can reach target tissues. Macrophage scavenger receptor SR type AI/II is the central phagocytic receptor that has been shown to promote in vitro uptake of many nanoparticle types. In this paper, the authors set out to clarify the role of SR-AI/II in the in vivo liver clearance of 10kDa dextran superparamagnetic iron oxide (SPIO) Feridex-IV® and 20kDa dextran-coated SPIO nanoworms (SPIO NWs). Feridex showed efficient SR-AI/II-dependent uptake by isolated KCs in vitro, whereas SPIO NWs showed no uptake by KCs. Both Feridex and SPIO NWs showed a very short and nearly identical circulation half-life and efficient uptake by KCs in vivo. The SR-AI/II inhibitor, polyinosinic acid, prolonged the circulation half-life of both Feridex and SPIO NWs, but did not reduce the KC uptake. The circulation half-life and KC uptake of Feridex and SPIO NWs were identical in SR-AI/II-deficient mice and wild-type mice. These data suggest: (1) there is a limited correlation between in vitro and in vivo uptake mechanisms of nanoparticles in KCs; and (2) redundant, SR-AI/II independent mechanisms play a significant role in the nanoparticle recognition by KCs in vivo. Understanding the complexity of nanoparticle clearance assays and mechanisms is an important step to improving the design of “stealthy” nanoparticles.

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Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion

Blood ◽

10.1182/blood-2009-08-236711 ◽

2010 ◽

Vol 115 (2) ◽

pp. 353-362 ◽

Cited By ~ 118

Author(s):

Audrey Varin ◽

Subhankar Mukhopadhyay ◽

Georges Herbein ◽

Siamon Gordon

Keyword(s):

Host Defense ◽

Scavenger Receptor ◽

Parasitic Infection ◽

Mitogen Activated Protein Kinase ◽

Interleukin 4 ◽

Alternative Activation ◽

Alternatively Activated Macrophages ◽

Stimulation Of

Abstract Alternatively activated macrophages play an important role in host defense in the context of a T helper type 2 (Th2) microenvironment such as parasitic infection. However, the role of these macrophages during secondary challenge with Th1 pathogens is poorly defined. In this study, thioglycollate-elicited mouse peritoneal macrophages were treated with interleukin-4 (IL-4) or IL-13 in vitro and challenged with Neisseria meningitidis. After 8 to 12 hours of IL-4 pretreatment, the nonopsonic phagocytic uptake of N meningitidis was markedly reduced, depending on the common IL-4Rα chain, but independent of Scavenger receptor A and macrophage receptor with collagenous structure (MARCO), 2 known receptors for N meningitidis. Inhibition of phagocytosis extended to several other microbial particles, zymosan, and other bacteria. Concomitantly, IL-4 potentiated the secretion of proinflammatory cytokines, after additional bacterial stimulation, which depended on the MyD88 signaling pathway. Similar results were obtained after intraperitoneal stimulation of IL-4 and N meningitidis in vivo. Further in vitro studies showed a striking correlation with inhibition of Akt phosphorylation and stimulation of the mitogen-activated protein kinase pathway; inhibition of phagocytosis was associated with inhibition of phagosome formation. These findings are relevant to host defense in mixed infections within a Th2 microenvironment and shed light on immunologic functions associated with alternative priming and full activation of macrophages.

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Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22052530 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2530

Author(s):

Bijean D. Ford ◽

Diego Moncada Giraldo ◽

Camilla Margaroli ◽

Vincent D. Giacalone ◽

Milton R. Brown ◽

...

Keyword(s):

Cystic Fibrosis ◽

Bactericidal Activity ◽

Scavenger Receptor ◽

Receptor Expression ◽

Blood Monocytes ◽

Bacterial Killing ◽

Blood Neutrophils ◽

Vitro Model

Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection.

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Mechanistic Fingerprinting Reveals Kinetic Signatures of Resistance to Daptomycin and Host Defense Peptides in Streptococcus mitis-oralis

Antibiotics ◽

10.3390/antibiotics10040404 ◽

2021 ◽

Vol 10 (4) ◽

pp. 404

Author(s):

Michael R. Yeaman ◽

Liana C. Chan ◽

Nagendra N. Mishra ◽

Arnold S. Bayer

Keyword(s):

Flow Cytometry ◽

Host Defense ◽

Durable Resistance ◽

Cross Resistance ◽

Streptococcus Mitis ◽

Host Defense Peptides ◽

Strain Pair ◽

Defense Peptides

Streptococcus mitis-oralis (S. mitis-oralis) infections are increasingly prevalent in specific populations, including neutropenic cancer and endocarditis patients. S. mitis-oralis strains have a propensity to evolve rapid, high-level and durable resistance to daptomycin (DAP-R) in vitro and in vivo, although the mechanism(s) involved remain incompletely defined. We examined mechanisms of DAP-R versus cross-resistance to cationic host defense peptides (HDPs), using an isogenic S. mitis-oralis strain-pair: (i) DAP-susceptible (DAP-S) parental 351-WT (DAP MIC = 0.5 µg/mL), and its (ii) DAP-R variant 351-D10 (DAP MIC > 256 µg/mL). DAP binding was quantified by flow cytometry, in-parallel with temporal (1–4 h) killing by either DAP or comparative prototypic cationic HDPs (hNP-1; LL-37). Multicolor flow cytometry was used to determine kinetic cell responses associated with resistance or susceptibility to these molecules. While overall DAP binding was similar between strains, a significant subpopulation of 351-D10 cells hyper-accumulated DAP (>2–4-fold vs. 351-WT). Further, both DAP and hNP-1 induced cell membrane (CM) hyper-polarization in 351-WT, corresponding to significantly greater temporal DAP-killing (vs. 351-D10). No strain-specific differences in CM permeabilization, lipid turnover or regulated cell death were observed post-exposure to DAP, hNP-1 or LL-37. Thus, the adaptive energetics of the CM appear coupled to the outcomes of interactions of S. mitis-oralis with DAP and selected HDPs. In contrast, altered CM permeabilization, proposed as a major mechanism of action of both DAP and HDPs, did not differentiate DAP-S vs. DAP-R phenotypes in this S. mitis-oralis strain-pair.

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A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1718902115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5076-E5085 ◽

Cited By ~ 40

Author(s):

Vu L. Ngo ◽

Hirohito Abo ◽

Estera Maxim ◽

Akihito Harusato ◽

Duke Geem ◽

...

Keyword(s):

Host Defense ◽

Immune Cells ◽

Intracellular Signaling ◽

Intestinal Barrier ◽

Intestinal Damage ◽

Cytokine Network ◽

Potent Inducer ◽

Intracellular Signaling Cascade

The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36γ is a potent inducer of IL-23 both in vitro and in vivo. IL-36γ–induced IL-23 required Notch2-dependent (CD11b+CD103+) dendritic cells (DCs), but not Batf3-dependent (CD11b−CD103+) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-κB subunits c-Rel and p50. Consistent with in vitro observations, IL-36R– and IL-36γ–deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R or IL-36γ could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36γ, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense.

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Molecular Flypaper, Atherosclerosis, and Host Defense: Structure and Function of the Macrophage Scavenger Receptor

Cold Spring Harbor Symposia on Quantitative Biology ◽

10.1101/sqb.1992.057.01.066 ◽

1992 ◽

Vol 57 (0) ◽

pp. 605-609 ◽

Cited By ~ 11

Author(s):

M. Krieger ◽

J.M. Abrams ◽

A. Lux ◽

H. Steller

Keyword(s):

Host Defense ◽

Scavenger Receptor ◽

Structure And Function ◽

Macrophage Scavenger Receptor ◽

And Function

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The Macrophage Scavenger Receptor Type A Is Expressed by Activated Macrophages and Protects the Host Against Lethal Endotoxic Shock

Journal of Experimental Medicine ◽

10.1084/jem.186.9.1431 ◽

1997 ◽

Vol 186 (9) ◽

pp. 1431-1439 ◽

Cited By ~ 202

Author(s):

Richard Haworth ◽

Nick Platt ◽

Satish Keshav ◽

Derralynn Hughes ◽

Elisabeth Darley ◽

...

Keyword(s):

Host Defense ◽

Bacterial Infections ◽

Endotoxic Shock ◽

Scavenger Receptor ◽

Type A ◽

Lipoteichoic Acid ◽

Protective Role ◽

Infection Model ◽

Macrophage Scavenger Receptor ◽

Tnf Α

During gram-negative bacterial infections, lipopolysaccharide (LPS) stimulates primed macrophages (Mφ) to release inflammatory mediators such as tumor necrosis factor (TNF)-α, which can cause hypotension, organ failure, and often death. Several different receptors on Mφ have been shown to bind LPS, including the type A scavenger receptor (SR-A). This receptor is able to bind a broad range of polyanionic ligands such as modified lipoproteins and lipoteichoic acid of gram-positive bacteria, which suggests that SR-A plays a role in host defense. In this study, we used mice lacking the SR-A (SRKO) to investigate the role of SR-A in acquired immunity using a viable bacillus Calmette Guérin (BCG) infection model. We show that activated Mφ express SR-A and that this molecule is functional in assays of adhesion and endocytic uptake. After BCG infection, SRKO mice are able to recruit Mφ to sites of granuloma formation where they become activated and restrict BCG replication. However, infected mice lacking the SR-A are more susceptible to endotoxic shock and produce more TNF-α and interleukin-6 in response to LPS. In addition, we show that an antibody which blocks TNF-α activity reduces LPS-induced mortality in these mice. Thus SR-A, expressed by activated Mφ, plays a protective role in host defense by scavenging LPS as well as by reducing the release by activated Mφ of proinflammatory cytokines. Modulation of SR-A may provide a novel therapeutic approach to control endotoxic shock.

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Impaired functional activity of alveolar macrophages from GM-CSF-deficient mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.281.5.l1210 ◽

2001 ◽

Vol 281 (5) ◽

pp. L1210-L1218 ◽

Cited By ~ 56

Author(s):

Robert Paine ◽

Susan B. Morris ◽

Hong Jin ◽

Steven E. Wilcoxen ◽

Susan M. Phare ◽

...

Keyword(s):

Host Defense ◽

Alveolar Macrophages ◽

Phagocytic Activity ◽

Wild Type ◽

Specific Expression ◽

Gm Csf ◽

Functional Capabilities ◽

Tnf Α

We hypothesized that pulmonary granulocyte-macrophage colony-stimulating factor (GM-CSF) is critically involved in determining the functional capabilities of alveolar macrophages (AM) for host defense. To test this hypothesis, cells were collected by lung lavage from GM-CSF mutant mice [GM(−/−)] and C57BL/6 wild-type mice. GM(−/−) mice yielded almost 4-fold more AM than wild-type mice. The percentage of cells positive for the β2-integrins CD11a and CD11c was reduced significantly in GM(−/−) AM compared with wild-type cells, whereas expression of CD11b was similar in the two groups. The phagocytic activity of GM(−/−) AM for FITC-labeled microspheres was impaired significantly compared with that of wild-type AM both in vitro and in vivo (after intratracheal inoculation with FITC-labeled beads). Stimulated secretion of tumor necrosis factor-α (TNF-α) and leukotrienes by AM from the GM(−/−) mice was greatly reduced compared with wild-type AM, whereas secretion of monocyte chemoattractant protein-1 was increased. Transgenic expression of GM-CSF exclusively in the lungs of GM(−/−) mice resulted in AM with normal or supranormal expression of CD11a and CD11c, phagocytic activity, and TNF-α secretion. Thus, in the absence of GM-CSF, AM functional capabilities for host defense were significantly impaired but were restored by lung-specific expression of GM-CSF.

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Peptide polymer displaying potent activity against clinically isolated multidrug resistant Pseudomonas aeruginosa in vitro and in vivo

Biomaterials Science ◽

10.1039/c9bm01726g ◽

2020 ◽

Vol 8 (2) ◽

pp. 739-745 ◽

Cited By ~ 11

Author(s):

Weinan Jiang ◽

Ximian Xiao ◽

Yueming Wu ◽

Weiwei Zhang ◽

Zihao Cong ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Activity ◽

Host Defense ◽

Multidrug Resistant ◽

Host Defense Peptide

Host defense peptide mimicking peptide polymer displayed potent in vitro and in vivo antimicrobial activity against clinically isolated multidrug resistant Pseudomonas aeruginosa.

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