Fetal liver endothelium regulates the seeding of tissue-resident macrophages

Rantakari, Pia; Jäppinen, Norma; Lokka, Emmi; Mokkala, Elias; Gerke, Heidi; Peuhu, Emilia; Ivaska, Johanna; Elima, Kati; Auvinen, Kaisa; Salmi, Marko

doi:10.1038/nature19814

Cited by 72 publications

(83 citation statements)

References 49 publications

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“…B and Supporting Fig. ) . Both N6W and N12W animals exhibited similar proportions of KCs and Mos at D0.…”

Section: Resultsmentioning

confidence: 70%

Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

Wei

et al. 2019

Hepatology

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To understand the mechanism(s) of age‐dependent outcomes of hepatitis B virus (HBV) infection in humans, we previously established an age‐related HBV mouse model in which 6‐week‐old (N6W) C3H/HeN mice exhibited virus tolerance whereas 12‐week‐old (N12W) counterparts presented virus clearance. By investigating the hepatic myeloid cell dynamics in mice of these two ages, we aim to identify factors associated with HBV clearance. C3H/HeN mice were transfected with an HBV plasmid by hydrodynamic injection. Serum HBV markers were monitored weekly. Hepatic leucocyte populations and their cytokine/chemokine productions were examined at baseline, day 3 (D3), day 7 (D7), and day 14 after injection. C‐C chemokine receptor type 2 (CCR2) antagonist and clodronate (CLD) were respectively administered to N12W and N6W mice to study the roles of lymphocyte antigen 6 complex, locus C (Ly6C)+ monocytes and Kupffer cells (KCs) in viral clearance. N12W mice had a significantly higher number of TNF‐α–secreting Ly6C+ monocytes and fewer IL‐10–secreting KCs at D3 in the liver than their younger N6W counterparts after HBV transfection. In addition, the elevated number of interferon‐γ+TNF‐α+ CD8+ T cells at D7 was only seen in the older cohort. The enhanced Ly6C+ monocyte induction in N12W mice resulted from elevated C‐C motif chemokine ligand 2 (CCL2) secretion by hepatocytes. CCR2 antagonist administration hampered Ly6C+ monocyte recruitment and degree of KC reduction and delayed HBV clearance in N12W animals. Depletion of KCs by CLD liposomes enhanced Ly6C+ monocyte recruitment and accelerated HBV clearance in N6W mice. Conclusions: Ly6C+ monocytes and KCs may, respectively, represent the resistance and tolerance arms of host defenses. These two cell types play an essential role in determining HBV clearance/tolerance. Manipulation of these cells is a promising avenue for immunotherapy of HBV‐related liver diseases.

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“…B and Supporting Fig. ) . Both N6W and N12W animals exhibited similar proportions of KCs and Mos at D0.…”

Section: Resultsmentioning

confidence: 70%

Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

Wei

et al. 2019

Hepatology

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“…They occur in endothelial cells (EC) of capillaries and venules in select vascular beds (reviewed in). The diaphragms are thin protein barriers associated with endothelial specific microdomains (ie fenestrae, transendothelial channels, caveolae and vesiculo‐vacuolar organelles) with roles in the maintenance of vascular permeability, blood/tissue homeostasis and the immune function …”

Section: Introductionmentioning

confidence: 99%

Phorbol esters induce PLVAP expression via VEGF and additional secreted molecules in MEK1‐dependent and p38, JNK and PI3K/Akt‐independent manner

Hamilton

Tse

Stan

2018

J Cellular Molecular Medi

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Endothelial diaphragms are subcellular structures critical for mammalian survival with poorly understood biogenesis. Plasmalemma vesicle associated protein (PLVAP) is the only known diaphragm component and is necessary for diaphragm formation. Very little is known about PLVAP regulation. Phorbol esters (PMA) are known to induce de novo PLVAP expression and diaphragm formation. We show that this induction relies on the de novo production of soluble factors that will act in an autocrine manner to induce PLVAP transcription and protein expression. We identified vascular endothelial growth factor‐A (VEGF‐A) signalling through VEGFR2 as a necessary but not sufficient downstream event as VEGF‐A inhibition with antibodies and siRNA or pharmacological inhibition of VEGFR2 only partially inhibit PLVAP upregulation. In terms of downstream pathways, inhibition of MEK1/Erk1/2 MAP kinase blocked PLVAP upregulation, whereas inhibition of p38 and JNK MAP kinases or PI3K and Akt had no effect on PMA‐induced PLVAP expression. In conclusion, we show that VEGF‐A along with other secreted proteins act synergistically to up‐regulate PLVAP in MEK1/Erk1/2 dependent manner, bringing us one step further into understanding the genesis of the essential structures that are endothelial diaphragms.

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“…During later embryonic stage, macrophages can be produced by fetal liver monocytes. Seeding of fetal liver monocytes in different tissues depends on plasmalemmal vesicle-associated protein [22]. Macrophages can also be derived from bone marrow-derived monocytes at steady state.…”

Section: Origin Of Monocytes and Macrophagesmentioning

confidence: 99%

Origin and production of inflammatory perivascular macrophages in pulmonary hypertension

Florentin

Dutta

2017

Cytokine

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Myeloid cells, including monocytes and macrophages participate in steady state immune homeostasis and help mount the adaptive immune response during infection. The function and production of these cells in sterile inflammation, such as pulmonary hypertension (PH), is understudied. Emerging data indicate that pulmonary inflammation mediated by lung perivascular macrophages is a key pathogenic driver of pulmonary remodeling leading to increased right ventricular systolic pressure (RVSP). However, the origin of these macrophages in pulmonary inflammation is unknown. Inflammatory monocytes, the precursors of pathogenic macrophages, are derived from hematopoietic stem and progenitor cells (HSPC) in the bone marrow and spleen during acute and chronic inflammation. Understanding the role of these organs in monocytopoiesis, and the mechanisms of HSPC proliferation and differentiation in PH are important to discover therapeutic targets curbing inflammation. This review will summarize the current limited knowledge of the origin of lung macrophage subsets and over-production of inflammatory monocytes in PH.

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Fetal liver endothelium regulates the seeding of tissue-resident macrophages

Cited by 72 publications

References 49 publications

Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

Lymphocyte Antigen 6 Complex, Locus C+ Monocytes and Kupffer Cells Orchestrate Liver Immune Responses Against Hepatitis B Virus in Mice

Phorbol esters induce PLVAP expression via VEGF and additional secreted molecules in MEK1‐dependent and p38, JNK and PI3K/Akt‐independent manner

Origin and production of inflammatory perivascular macrophages in pulmonary hypertension

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