Desialylated LDL uptake in human and mouse macrophages can be mediated by a lectin receptor

Acute-on-chronic liver failure (ACLF) carries a significant burden on critical care services and health care resources. However, the exact pathogenesis of ACLF remains to be elucidated, and novel treatments are desperately required. In our previous work, we utilized mice subjected to acute insult in the context of hepatic fibrosis to simulate the development of ACLF and documented the favorable hepatoprotection conferred by M2-like macrophages in vivo and in vitro. In the present study, we focused on the phenotypic switch of human and mouse macrophages and assessed the effects of this switch on apoptosis resistance in hepatocytes. For this purpose, human and mouse macrophages were isolated and polarized into M0, M(IFN-γ), M(IFN-γ→IL-4), M(IL-4) or M(IL-4→IFN-γ) subsets. Conditioned media (CM) from these subsets were applied to human and mouse hepatocytes followed by apoptosis induction. Cell apoptosis was evaluated by immunostaining for cleaved caspase-3. As a result, M(IFN-γ) or M(IL-4) macrophages switched their phenotype into M(IFN-γ→IL-4) or M(IL-4→IFN-γ) through reprogramming with IL-4 or IFN-γ, respectively. Importantly, hepatocytes pre-treated with M(IFN-γ→IL-4) CMs exhibited much weaker expression of cleaved caspase-3, compared to those pre-treated with M(IFN-γ) CM, and vice versa. Together, phenotypic switch of macrophages toward M(IL-4) phenotype confers hepatocytes enhanced resistance to apoptosis.

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Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences

Blood ◽

10.1182/blood-2012-06-436212 ◽

2013 ◽

Vol 121 (9) ◽

pp. e57-e69 ◽

Cited By ~ 277

Author(s):

Fernando O. Martinez ◽

Laura Helming ◽

Ronny Milde ◽

Audrey Varin ◽

Barbro N. Melgert ◽

...

Keyword(s):

M2 Macrophages ◽

Human Macrophages ◽

Key Points ◽

Gene And Protein Expression ◽

Activated State ◽

Mouse Macrophages ◽

Similarities And Differences ◽

Conserved Gene ◽

Human And Mouse ◽

Alternatively Activated

Key Points Human and mouse macrophages share partially conserved gene and protein expression programs in the resting or M2 activated state. TGM2 is a novel M2 marker consistently induced in human and mouse M2 macrophages.

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SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway

10.1101/2021.03.16.435700 ◽

2021 ◽

Author(s):

Shahanshah Khan ◽

Mahnoush S. Shafiei ◽

Christopher Longoria ◽

John Schoggins ◽

Rashmin C. Savani ◽

...

Keyword(s):

Epithelial Cells ◽

Inflammatory Response ◽

Inflammatory Cytokines ◽

Lung Epithelial Cells ◽

Dependent Manner ◽

S Protein ◽

Cytokines And Chemokines ◽

Lung Epithelial ◽

Mouse Macrophages ◽

Human And Mouse

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1b, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-kB pathway in a MyD88-dependent manner. Further, such an activation of the NF-kB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1b in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

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Development of a cell system for siRNA screening of pathogen responses in human and mouse macrophages

Scientific Reports ◽

10.1038/srep09559 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 12

Author(s):

Ning Li ◽

Jing Sun ◽

Zachary L. Benet ◽

Ze Wang ◽

Souhaila Al-Khodor ◽

...

Keyword(s):

Cell System ◽

Mouse Macrophages ◽

A Cell ◽

Human And Mouse ◽

Sirna Screening

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Enhancement of Innate Immunity againstMycobacterium avium Infection by Immunostimulatory DNA Is Mediated by Indoleamine 2,3-Dioxygenase

Infection and Immunity ◽

10.1128/iai.69.10.6156-6164.2001 ◽

2001 ◽

Vol 69 (10) ◽

pp. 6156-6164 ◽

Cited By ~ 49

Author(s):

Tomoko Hayashi ◽

Savita P. Rao ◽

Kenji Takabayashi ◽

John H. Van Uden ◽

Richard S. Kornbluth ◽

...

Keyword(s):

Innate Immunity ◽

Cytotoxic T Lymphocyte ◽

Interleukin 12 ◽

Necrosis Factor Alpha ◽

Indoleamine 2,3 Dioxygenase ◽

Mouse Macrophages ◽

Avium Infection ◽

Human And Mouse

ABSTRACT Bacterial DNA and its synthetic immunostimulatory oligodeoxynucleotide analogs (ISS-ODN) activate innate immunity and promote Th1 and cytotoxic T-lymphocyte immune responses. Based on these activities, we investigated whether ISS-ODN could modify the course ofMycobacterium avium infection. M. aviumgrowth in vitro was significantly inhibited by ISS-ODN treatment of human and mouse macrophages, and M. avium growth in vivo was similarly inhibited in C57BL/6 mice treated with ISS-ODN. This protective effect of ISS-ODN was largely independent of tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), nitric oxide, NADPH oxidase, alpha/beta interferon (IFN-α/β), and IFN-γ. In contrast, we found that the induction of indoleamine 2,3-dioxygenase (IDO) was required for the antimycobacterial effect of ISS-ODN. To evaluate the potential for synergism between ISS-ODN and other antimycobacterial agents, treatment with a combination of ISS-ODN and clarithromycin (CLA) was tested in vitro and in vivo. ISS-ODN significantly enhanced the therapeutic effect of CLA in both human and mouse macrophages and in C57BL/6 mice. This study newly identifies IDO as being involved in the antimicrobial activity of ISS-ODN and suggests the usefulness of ISS-ODN when used in combination with conventional chemotherapy for microbial infections.

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Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state

Journal of Experimental Medicine ◽

10.1084/jem.20071733 ◽

2007 ◽

Vol 204 (13) ◽

pp. 3133-3146 ◽

Cited By ~ 325

Author(s):

Florent Ginhoux ◽

Matthew P. Collin ◽

Milena Bogunovic ◽

Michal Abel ◽

Marylene Leboeuf ◽

...

Keyword(s):

Dendritic Cells ◽

Steady State ◽

Langerhans Cells ◽

Current View ◽

Lectin Receptor ◽

Bone Marrow Chimeras ◽

Human And Mouse ◽

Draining Lymph Nodes ◽

Epidermal Langerhans Cells

Langerin is a C-type lectin receptor that recognizes glycosylated patterns on pathogens. Langerin is used to identify human and mouse epidermal Langerhans cells (LCs), as well as migratory LCs in the dermis and the skin draining lymph nodes (DLNs). Using a mouse model that allows conditional ablation of langerin+ cells in vivo, together with congenic bone marrow chimeras and parabiotic mice as tools to differentiate LC- and blood-derived dendritic cells (DCs), we have revisited the origin of langerin+ DCs in the skin DLNs. Our results show that in contrast to the current view, langerin+CD8− DCs in the skin DLNs do not derive exclusively from migratory LCs, but also include blood-borne langerin+ DCs that transit through the dermis before reaching the DLN. The recruitment of circulating langerin+ DCs to the skin is dependent on endothelial selectins and CCR2, whereas their recruitment to the skin DLNs requires CCR7 and is independent of CD62L. We also show that circulating langerin+ DCs patrol the dermis in the steady state and migrate to the skin DLNs charged with skin antigens. We propose that this is an important and previously unappreciated element of immunosurveillance that needs to be taken into account in the design of novel vaccine strategies.

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Phospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2112971118 ◽

2021 ◽

Vol 118 (41) ◽

pp. e2112971118

Author(s):

Hui Jing ◽

Alex Reed ◽

Olesya A. Ulanovskaya ◽

Jan-Sebastian Grigoleit ◽

Dylan M. Herbst ◽

...

Keyword(s):

Cross Talk ◽

Immune Cells ◽

Receptor Activation ◽

Innate Immune ◽

Innate Immune Cells ◽

Genetic Studies ◽

Mouse Macrophages ◽

Inflammatory Stimuli ◽

And Function ◽

Human And Mouse

Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase Cγ2 (PLCγ2 or PLCG2)—mutations in which are associated with autoinflammatory disorders and Alzheimer’s disease—serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2−/− mice showed generally normal proinflammatory cytokine and chemokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in cross-talk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli.

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Human and Mouse Macrophages Collaborate with Neutrophils To Kill Larval Strongyloides stercoralis

Infection and Immunity ◽

10.1128/iai.00625-13 ◽

2013 ◽

Vol 81 (9) ◽

pp. 3346-3355 ◽

Cited By ~ 48

Author(s):

Sandra Bonne-Année ◽

Laura A. Kerepesi ◽

Jessica A. Hess ◽

Amy E. O'Connell ◽

James B. Lok ◽

...

Keyword(s):

Strongyloides Stercoralis ◽

Activated Macrophages ◽

Alternatively Activated Macrophages ◽

Parasitic Helminths ◽

Time Period ◽

Mouse Macrophages ◽

Classically Activated Macrophages ◽

Human And Mouse

ABSTRACTMacrophages are multifunctional cells that are active in TH1- and TH2-mediated responses. In this study, we demonstrate that human and mouse macrophages collaborate with neutrophils and complement to kill the parasiteStrongyloides stercoralis in vitro. Infection of mice with worms resulted in the induction of alternatively activated macrophages (AAMϕ) within the peritoneal cavity. These cells killed the wormsin vivoand collaborated with neutrophils and complement during thein vitrokilling process. AAMϕ generatedin vitrokilled larvae more rapidly than naive macrophages, which killed larvae after a longer time period. In contrast, classically activated macrophages were unable to kill larvae eitherin vitroorin vivo. This study adds macrophages to the armamentarium of immune components that function in elimination of parasitic helminths and demonstrate a novel function by which AAMϕ control large extracellular parasites.

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