Interferon-α mRNA in Splenic CD11b+ Marginal Zone Macrophages of C4-Deficient Mice

Zdhhc family genes are composed of 24 members that regulate palmitoylation, a post-translational modification process for proteins. Mutations in genes that alter palmitoylation or de-palmitoylation could result in neurodegenerative diseases and inflammatory disorders. In this study, we found that Zdhhc2 was robustly induced in psoriatic skin and loss of Zdhhc2 in mice by CRISPR/Cas9 dramatically inhibited pathology of the ear skin following imiquimod treatment. As psoriasis is an inflammatory disorder, we analyzed tissue infiltrating immune cells and cytokine production. Strikingly we found that a master psoriatic cytokine interferon-α (IFN-α) in the lesioned skin of wildtype (WT) mice was 23-fold higher than that in Zdhhc2 deficient counterparts. In addition, we found that CD45+ white blood cells (WBC) infiltrating in the skin of Zdhhc2 deficient mice were also significantly reduced. Amelioration in psoriasis and dramatically reduced inflammation of Zdhhc2 deficient mice led us to analyze the cellular components that were affected by loss of Zdhhc2. We found that imiquimod induced plasmacytoid dendritic cell (pDC) accumulation in psoriatic skin, spleen, and draining lymph nodes (DLN) were drastically decreased in Zdhhc2 deficient mice, and the expression of pDC activation marker CD80 also exhibited significantly inhibited in psoriatic skin. In further experiments, we confirmed the cell intrinsic effect of Zdhhc2 on pDCs as we found that loss of zDHHC2 in human CAL-1 pDC dampened both interferon regulatory factor 7 (IRF7) phosphorylation and IFN-α production. Therefore, we identified novel function of Zdhhc2 in controlling inflammatory response in psoriasis in mice and we also confirmed that crucial role of Zdhhc2 in pDCs by regulating IRF7 activity and production of the critical cytokine. Our results finding the dependence of IFN-α production on Zdhhc2 in inflamed murine skin and in human pDCs provide rationale for targeting this new molecule in treatment of inflammation.

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Vav proteins regulate peripheral B-cell survival

Blood ◽

10.1182/blood-2004-12-4894 ◽

2005 ◽

Vol 106 (7) ◽

pp. 2391-2398 ◽

Cited By ~ 33

Author(s):

Elena Vigorito ◽

Laure Gambardella ◽

Francesco Colucci ◽

Simon McAdam ◽

Martin Turner

Keyword(s):

B Cells ◽

B Cell ◽

Marginal Zone ◽

Cell Receptor ◽

Cross Linking ◽

Marginal Zone B Cells ◽

Survival Signal ◽

B Cell Survival ◽

Follicular B Cells ◽

Deficient Mice

AbstractMice lacking all 3 Vav proteins fail to produce significant numbers of recirculating follicular or marginal zone B cells. Those B cells that do mature have shortened lifespans. The constitutive nuclear factor-kappaB (NF-κB) activity of resting naive B cells required Vav function and expression of cellular reticuloendotheliosis (c-Rel). Rel-A was reduced in Vav-deficient B cells. Furthermore, expression of the NF-κB-regulated antiapoptotic genes A1 and Bcl-2 was reduced in mature Vav-deficient B cells. Overexpression of Bcl-2 restored the number of mature follicular B cells in the spleens of Vav-deficient mice. When activated by B-cell receptor (BCR) cross-linking, Vav-deficient B cells failed to activate NF-κB. Vav proteins thus regulate an NF-κB-dependent survival signal in naive B cells and are required for NF-κB function after BCR cross-linking.

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Exacerbated Imiquimod-Induced Psoriasis-Like Skin Inflammation in IRF5-Deficient Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21103681 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3681

Author(s):

Momoko Nakao ◽

Tomomitsu Miyagaki ◽

Makoto Sugaya ◽

Shinichi Sato

Keyword(s):

Critical Role ◽

Skin Inflammation ◽

Interferon Α ◽

Toll Like Receptor ◽

Adaptive Immune ◽

Th17 Cytokines ◽

Factor Α ◽

Deficient Mice ◽

Necrosis Factor

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.

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Cutting Edge: Marginal Zone Macrophages Regulate Antigen Transport by B Cells to the Follicle in the Spleen via CD21

The Journal of Immunology ◽

10.4049/jimmunol.1502282 ◽

2016 ◽

Vol 197 (6) ◽

pp. 2063-2068 ◽

Cited By ~ 4

Author(s):

Kajsa E. Prokopec ◽

Anna-Maria Georgoudaki ◽

Silke Sohn ◽

Fredrik Wermeling ◽

Hans Grönlund ◽

...

Keyword(s):

B Cells ◽

Marginal Zone ◽

Cutting Edge ◽

Antigen Transport ◽

Marginal Zone Macrophages

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Crucial role of Mer tyrosine kinase in the maintenance of SIGN-R1+ marginal zone macrophages

Immunology and Cell Biology ◽

10.1111/imcb.12003 ◽

2018 ◽

Vol 96 (3) ◽

pp. 298-315

Author(s):

Chetna Soni ◽

Stephanie L Schell ◽

Melinda J Fasnacht ◽

Sathi Babu Chodisetti ◽

Ziaur SM Rahman

Keyword(s):

Tyrosine Kinase ◽

Crucial Role ◽

Marginal Zone ◽

Mer Tyrosine Kinase ◽

Marginal Zone Macrophages

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Effects of lethal and non-lethal malaria on the mononuclear phagocyte system

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86821983000100008 ◽

1983 ◽

Vol 16 (1) ◽

pp. 58-67 ◽

Cited By ~ 9

Author(s):

Carlos Eduardo Tosta ◽

Greta Ruiz ◽

Nina Wedderburn

Keyword(s):

Marginal Zone ◽

Plasmodium Yoelii ◽

Mononuclear Phagocyte ◽

Mononuclear Phagocyte System ◽

Phagocytic Cells ◽

Terminal Stage ◽

Haematopoietic Tissue ◽

Red Pulp ◽

Marginal Zone Macrophages

The effects ofone non-lethal species ofmalarialparasite, Plasmodium yoelii, and one lethal species, P. berghei, on the mononuclear phagocyte system (MPS) of BALB/c mice were studied. P. yoelii caused a greater and more sustained expansion and activation of the MPS, and the two major populations of spleen phagocytic cells-red pulp and marginal zone macrophages - exhibited a greater increase in numbers in this infection. During the course of P. berghei mataria, the spleen was progressively occupied by haematopoietic tissue and, at the terminal stage of infection, an extensive depletion of lymphocytes and macrophages was apparent. The possibility was suggested that the outcome of mataria may be inftuenced by the particular way the parasite interacts with the MPS.

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Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo

Blood ◽

10.1182/blood-2002-04-1044 ◽

2002 ◽

Vol 100 (8) ◽

pp. 2908-2916 ◽

Cited By ~ 135

Author(s):

Teunis B. H. Geijtenbeek ◽

Peter C. Groot ◽

Martijn A. Nolte ◽

Sandra J. van Vliet ◽

Shanti T. Gangaram-Panday ◽

...

Keyword(s):

Marginal Zone ◽

Synapse Formation ◽

Intercellular Adhesion Molecule ◽

Pathogen Recognition ◽

Liver Sinusoidal Endothelial Cells ◽

Specific Polysaccharide ◽

Murine Homologue ◽

Encapsulated Bacteria ◽

Marginal Zone Macrophages

Antigen-presenting cells are localized in essentially every tissue, where they operate at the interface of innate and acquired immunity by capturing pathogens and presenting pathogen-derived peptides to T cells. C-type lectins are important pathogen recognition receptors and the C-type lectin, dendritic cell–specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN), is unique in that, in addition to pathogen capture, it regulates adhesion processes such as DC trafficking and T-cell synapse formation. We have isolated a murine homologue of DC-SIGN that is identical to the previously reported murine homologue mSIGNR1. mSIGNR1 is more closely related to the human DC-SIGN homologue L-SIGN than to DC-SIGN itself because mSIGNR1 is specifically expressed by liver sinusoidal endothelial cells, similar to L-SIGN, and not by DCs. Moreover, mSIGNR1 is also expressed by medullary and subcapsular macrophages in lymph nodes and by marginal zone macrophages (MZMs) in the spleen. Strikingly, these MZMs are in direct contact with the bloodstream and efficiently capture specific polysaccharide antigens present on the surface of encapsulated bacteria. We have investigated the in vivo function of mSIGNR1 on MZMs in spleen. We demonstrate here that mSIGNR1 functions in vivo as a pathogen recognition receptor on MZMs that capture blood-borne antigens, which are rapidly internalized and targeted to lysosomes for processing. Moreover, the antigen capture is completely blocked in vivo by the blocking mSIGNR1-specific antibodies. Thus, mSIGNR1, a murine homologue of DC-SIGN, is important in the defense against pathogens and this study will facilitate further investigations into the in vivo function of DC-SIGN and its homologues.

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Roles of a Macrophage Receptor with Collagenous Structure(MARCO) in Host Defense and Heterogeneity of Splenic Marginal Zone Macrophages.

Archives of Histology and Cytology ◽

10.1679/aohc.62.83 ◽

1999 ◽

Vol 62 (1) ◽

pp. 83-95 ◽

Cited By ~ 43

Author(s):

Shigeo ITO ◽

Makoto NAITO ◽

Yoshiaki KOBAYASHI ◽

Hisakazu TAKATSUKA ◽

Shuying JIANG ◽

...

Keyword(s):

Host Defense ◽

Marginal Zone ◽

Collagenous Structure ◽

Marginal Zone Macrophages

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Interaction of SIGNR1 expressed by marginal zone macrophages with marginal zone B cells is essential to early IgM responses against Streptococcus pneumoniae

Molecular Immunology ◽

10.1016/j.molimm.2008.01.032 ◽

2008 ◽

Vol 45 (10) ◽

pp. 2881-2887 ◽

Cited By ~ 33

Author(s):

Estella A. Koppel ◽

Manja Litjens ◽

Venice C. van den Berg ◽

Yvette van Kooyk ◽

Teunis B.H. Geijtenbeek

Keyword(s):

Streptococcus Pneumoniae ◽

B Cells ◽

Marginal Zone ◽

Marginal Zone B Cells ◽

Marginal Zone Macrophages

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Cas-L/Hef1 Is Required for Marginal Zone B Cell Maintenance and Lymphocyte Trafficking.

Blood ◽

10.1182/blood.v106.11.3920.3920 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3920-3920

Author(s):

Sachiko Seo ◽

Takashi Asai ◽

Toshiki Saito ◽

Takahiro Suzuki ◽

Motoshi Ichikawa ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Marginal Zone ◽

Cell Receptor ◽

Cell Number ◽

Lymphoid Organs ◽

Adhesion Assay ◽

Lymphocyte Migration ◽

Lymphocyte Trafficking ◽

Deficient Mice

Abstract Cas-L (Crk-associated substrate lymphocyte type) which is also known as Hef1 (human enhancer of filamentation 1) was first identified as a protein tyrosine-phosphorylated upon stimulation of b1 integrin. Cas-L possesses a single Src homology (SH) 3 domain and multiple YXXP motifs (substrate domain) as a member of Cas protein family, and is well expressed in peripheral lymphocytes. Previous studies suggest that Cas-L might be involved in Bcr-Abl positive leukemia and adult T cell leukemia. However, the biological function of Cas-L in lymphocytes is little known. We generated Cas-L-deficient mice using a gene targeting strategy. The mice showed a deficit of marginal zone (MZ) B cells and a decrease of cell number in secondary lymphoid organs. To elucidate the mechanism of the MZ B cell defect, the reciprocal bone marrow transfer assays were performed. The results revealed that the defect of MZ B cells in Cas-L-deficient mice is cell autonomous. Next, we analyzed B cell receptor signaling by measurement of intracellular Ca2+ concentration and lymphocyte proliferation. However, we could not find any significant differences between wild type and Cas-L-deficient mice. Cas-L-deficient lymphocytes showed reduced chemotactic response to CXCL12 and CXCL13. The adhesion assay also showed the decreased adhesiveness to VCAM-1 and ICAM-1, which are important for retention of MZ B cells in spleen. Moreover, we found that the lymphocyte trafficking to spleen and lymph nodes was altered in Cas-L-deficient mice. Thus, Cas-L affects homeostasis of MZ B cells and peripheral lymphoid organs, which is considered to be relevant to impaired lymphocyte migration and adhesion.

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