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CLEC4F is an inducible C-type lectin in F4/80-positive cells and is involved in alpha-galactosylceramide presentation in liver.

Yang CY, Chen JB, Tsai TF, Tsai YC, Tsai CY, Liang PH, Hsu TL, Wu CY, Netea MG, Wong CH, Hsieh SL - PLoS ONE (2013)

Bottom Line: We found that CLEC4F is a heavily glycosylated membrane protein co-expressed with F4/80 on Kupffer cells.Moreover, CLEC4F interacts with alpha-galactosylceramide (α-GalCer) in a calcium-dependent manner and participates in the presentation of α-GalCer to natural killer T (NKT) cells.This suggests that CLEC4F is a C-type lectin with diverse binding specificity expressed on residential Kupffer cells and infiltrating monocytes in the liver, and may play an important role to modulate glycolipids presentation on Kupffer cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT
CLEC4F, a member of C-type lectin, was first purified from rat liver extract with high binding affinity to fucose, galactose (Gal), N-acetylgalactosamine (GalNAc), and un-sialylated glucosphingolipids with GalNAc or Gal terminus. However, the biological functions of CLEC4F have not been elucidated. To address this question, we examined the expression and distribution of murine CLEC4F, determined its binding specificity by glycan array, and investigated its function using CLEC4F knockout (Clec4f-/-) mice. We found that CLEC4F is a heavily glycosylated membrane protein co-expressed with F4/80 on Kupffer cells. In contrast to F4/80, CLEC4F is detectable in fetal livers at embryonic day 11.5 (E11.5) but not in yolk sac, suggesting the expression of CLEC4F is induced as cells migrate from yolk cells to the liver. Even though CLEC4F is not detectable in tissues outside liver, both residential Kupffer cells and infiltrating mononuclear cells surrounding liver abscesses are CLEC4F-positive upon Listeria monocytogenes (L. monocytogenes) infection. While CLEC4F has strong binding to Gal and GalNAc, terminal fucosylation inhibits CLEC4F recognition to several glycans such as Fucosyl GM1, Globo H, Bb3∼4 and other fucosyl-glycans. Moreover, CLEC4F interacts with alpha-galactosylceramide (α-GalCer) in a calcium-dependent manner and participates in the presentation of α-GalCer to natural killer T (NKT) cells. This suggests that CLEC4F is a C-type lectin with diverse binding specificity expressed on residential Kupffer cells and infiltrating monocytes in the liver, and may play an important role to modulate glycolipids presentation on Kupffer cells.

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CLEC4F+ cells were appeared in the liver environment under Kupffer cell depletion and inflammatory stage.(A) Kupffer cells were depleted by Cl2MBP-encapsulated liposome by intravenous injection (100 µl/mouse) at day 0 and livers were harvest at day 1, 7, 14 and 28. F4/80 and CLEC4F immunohistochemistry of liver sections were performed. (B) The numbers of F4/80+ or CLEC4F+ cells in livers were shown. For generating inflammatory stage, wild-type and Clec4f−/− littermates were infected with L. monocytogenes (1×105 CFU/mouse) intravenously. (C) The numbers of F4/80+ or CLEC4F+ cells in livers during L. monocytogenes infection. (D) Immunohistochemistry of L. monocytogenes infected livers of wild-type and Clec4f−/− mice at day 5 after infection. (E) Kaplan-Meier survival curves were shown for Clec4f−/− or wild-type littermates with L. monocytogenes infection. The p value was determined by Log-rank test.
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pone-0065070-g004: CLEC4F+ cells were appeared in the liver environment under Kupffer cell depletion and inflammatory stage.(A) Kupffer cells were depleted by Cl2MBP-encapsulated liposome by intravenous injection (100 µl/mouse) at day 0 and livers were harvest at day 1, 7, 14 and 28. F4/80 and CLEC4F immunohistochemistry of liver sections were performed. (B) The numbers of F4/80+ or CLEC4F+ cells in livers were shown. For generating inflammatory stage, wild-type and Clec4f−/− littermates were infected with L. monocytogenes (1×105 CFU/mouse) intravenously. (C) The numbers of F4/80+ or CLEC4F+ cells in livers during L. monocytogenes infection. (D) Immunohistochemistry of L. monocytogenes infected livers of wild-type and Clec4f−/− mice at day 5 after infection. (E) Kaplan-Meier survival curves were shown for Clec4f−/− or wild-type littermates with L. monocytogenes infection. The p value was determined by Log-rank test.

Mentions: Since CLEC4F expression is restricted to Kupffer cells, we further compared the number of CLEC4F+ and F4/80+ cells in liver under reconstitution or inflammatory stage. Firstly, we examined the amount of CLEC4F+ and F4/80+ cells during Kupffer cell repopulation after intravenous administration of liposome-encapsulated dichloromethylene diphosphonate (Cl2MBP) (Figure 4A & 4B). Kupffer cells could be depleted after Cl2MBP-encapsulated liposome treatment and will repopulate over time [16], [17], [31]. At day 1 post Cl2MBP-encapsulated liposome injection, Kupffer cells were depleted completely and no any F4/80+ or CLEC4F+ cells were detectable in liver (Figure 4A). At day 3 post Cl2MBP-encapsulated liposome injection, both CLEC4F+ and F4/80+ cells reappeared, with similar number and distribution in the liver. The numbers of CLEC4F+ and F4/80+ cells further increased and restored to original levels at day 28. Figure 4B summarized the kinetic change in the number of hepatic CLEC4F+ and F4/80+ cells after Kupffer cell depletion by Cl2MBP-encapsulated liposome. This observation suggests that reconstituted Kupffer cells expressed both CLEC4F and F4/80 simultaneously.


CLEC4F is an inducible C-type lectin in F4/80-positive cells and is involved in alpha-galactosylceramide presentation in liver.

Yang CY, Chen JB, Tsai TF, Tsai YC, Tsai CY, Liang PH, Hsu TL, Wu CY, Netea MG, Wong CH, Hsieh SL - PLoS ONE (2013)

CLEC4F+ cells were appeared in the liver environment under Kupffer cell depletion and inflammatory stage.(A) Kupffer cells were depleted by Cl2MBP-encapsulated liposome by intravenous injection (100 µl/mouse) at day 0 and livers were harvest at day 1, 7, 14 and 28. F4/80 and CLEC4F immunohistochemistry of liver sections were performed. (B) The numbers of F4/80+ or CLEC4F+ cells in livers were shown. For generating inflammatory stage, wild-type and Clec4f−/− littermates were infected with L. monocytogenes (1×105 CFU/mouse) intravenously. (C) The numbers of F4/80+ or CLEC4F+ cells in livers during L. monocytogenes infection. (D) Immunohistochemistry of L. monocytogenes infected livers of wild-type and Clec4f−/− mice at day 5 after infection. (E) Kaplan-Meier survival curves were shown for Clec4f−/− or wild-type littermates with L. monocytogenes infection. The p value was determined by Log-rank test.
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Related In: Results  -  Collection

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pone-0065070-g004: CLEC4F+ cells were appeared in the liver environment under Kupffer cell depletion and inflammatory stage.(A) Kupffer cells were depleted by Cl2MBP-encapsulated liposome by intravenous injection (100 µl/mouse) at day 0 and livers were harvest at day 1, 7, 14 and 28. F4/80 and CLEC4F immunohistochemistry of liver sections were performed. (B) The numbers of F4/80+ or CLEC4F+ cells in livers were shown. For generating inflammatory stage, wild-type and Clec4f−/− littermates were infected with L. monocytogenes (1×105 CFU/mouse) intravenously. (C) The numbers of F4/80+ or CLEC4F+ cells in livers during L. monocytogenes infection. (D) Immunohistochemistry of L. monocytogenes infected livers of wild-type and Clec4f−/− mice at day 5 after infection. (E) Kaplan-Meier survival curves were shown for Clec4f−/− or wild-type littermates with L. monocytogenes infection. The p value was determined by Log-rank test.
Mentions: Since CLEC4F expression is restricted to Kupffer cells, we further compared the number of CLEC4F+ and F4/80+ cells in liver under reconstitution or inflammatory stage. Firstly, we examined the amount of CLEC4F+ and F4/80+ cells during Kupffer cell repopulation after intravenous administration of liposome-encapsulated dichloromethylene diphosphonate (Cl2MBP) (Figure 4A & 4B). Kupffer cells could be depleted after Cl2MBP-encapsulated liposome treatment and will repopulate over time [16], [17], [31]. At day 1 post Cl2MBP-encapsulated liposome injection, Kupffer cells were depleted completely and no any F4/80+ or CLEC4F+ cells were detectable in liver (Figure 4A). At day 3 post Cl2MBP-encapsulated liposome injection, both CLEC4F+ and F4/80+ cells reappeared, with similar number and distribution in the liver. The numbers of CLEC4F+ and F4/80+ cells further increased and restored to original levels at day 28. Figure 4B summarized the kinetic change in the number of hepatic CLEC4F+ and F4/80+ cells after Kupffer cell depletion by Cl2MBP-encapsulated liposome. This observation suggests that reconstituted Kupffer cells expressed both CLEC4F and F4/80 simultaneously.

Bottom Line: We found that CLEC4F is a heavily glycosylated membrane protein co-expressed with F4/80 on Kupffer cells.Moreover, CLEC4F interacts with alpha-galactosylceramide (α-GalCer) in a calcium-dependent manner and participates in the presentation of α-GalCer to natural killer T (NKT) cells.This suggests that CLEC4F is a C-type lectin with diverse binding specificity expressed on residential Kupffer cells and infiltrating monocytes in the liver, and may play an important role to modulate glycolipids presentation on Kupffer cells.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.

ABSTRACT
CLEC4F, a member of C-type lectin, was first purified from rat liver extract with high binding affinity to fucose, galactose (Gal), N-acetylgalactosamine (GalNAc), and un-sialylated glucosphingolipids with GalNAc or Gal terminus. However, the biological functions of CLEC4F have not been elucidated. To address this question, we examined the expression and distribution of murine CLEC4F, determined its binding specificity by glycan array, and investigated its function using CLEC4F knockout (Clec4f-/-) mice. We found that CLEC4F is a heavily glycosylated membrane protein co-expressed with F4/80 on Kupffer cells. In contrast to F4/80, CLEC4F is detectable in fetal livers at embryonic day 11.5 (E11.5) but not in yolk sac, suggesting the expression of CLEC4F is induced as cells migrate from yolk cells to the liver. Even though CLEC4F is not detectable in tissues outside liver, both residential Kupffer cells and infiltrating mononuclear cells surrounding liver abscesses are CLEC4F-positive upon Listeria monocytogenes (L. monocytogenes) infection. While CLEC4F has strong binding to Gal and GalNAc, terminal fucosylation inhibits CLEC4F recognition to several glycans such as Fucosyl GM1, Globo H, Bb3∼4 and other fucosyl-glycans. Moreover, CLEC4F interacts with alpha-galactosylceramide (α-GalCer) in a calcium-dependent manner and participates in the presentation of α-GalCer to natural killer T (NKT) cells. This suggests that CLEC4F is a C-type lectin with diverse binding specificity expressed on residential Kupffer cells and infiltrating monocytes in the liver, and may play an important role to modulate glycolipids presentation on Kupffer cells.

Show MeSH
Related in: MedlinePlus