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Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues.

Palframan RT, Jung S, Cheng G, Weninger W, Luo Y, Dorf M, Littman DR, Rollins BJ, Zweerink H, Rot A, von Andrian UH - J. Exp. Med. (2001)

Bottom Line: MCP-1 mRNA in inflamed skin was over 100-fold upregulated and paralleled MCP-1 protein levels, whereas in draining LNs MCP-1 mRNA induction was much weaker and occurred only after a pronounced rise in MCP-1 protein.Thus, MCP-1 in draining LNs was primarily derived from inflamed skin.These findings demonstrate that inflamed peripheral tissues project their local chemokine profile to HEVs in draining LNs and thereby exert "remote control" over the composition of leukocyte populations that home to these organs from the blood.

View Article: PubMed Central - PubMed

Affiliation: Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
Interstitial fluid is constantly drained into lymph nodes (LNs) via afferent lymph vessels. This conduit enables monocyte-derived macrophages and dendritic cells to access LNs from peripheral tissues. We show that during inflammation in the skin, a second recruitment pathway is evoked that recruits large numbers of blood-borne monocytes to LNs via high endothelial venules (HEVs). Inhibition of monocyte chemoattractant protein (MCP)-1 blocked this inflammation-induced monocyte homing to LNs. MCP-1 mRNA in inflamed skin was over 100-fold upregulated and paralleled MCP-1 protein levels, whereas in draining LNs MCP-1 mRNA induction was much weaker and occurred only after a pronounced rise in MCP-1 protein. Thus, MCP-1 in draining LNs was primarily derived from inflamed skin. In MCP-1(-/-) mice, intracutaneously injected MCP-1 accumulated rapidly in the draining LNs where it enhanced monocyte recruitment. Intravital microscopy showed that skin-derived MCP-1 was transported via the lymph to the luminal surface of HEVs where it triggered integrin-dependent arrest of rolling monocytes. These findings demonstrate that inflamed peripheral tissues project their local chemokine profile to HEVs in draining LNs and thereby exert "remote control" over the composition of leukocyte populations that home to these organs from the blood.

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Related in: MedlinePlus

MCP-1 accumulates in HEVs after intracutaneous injection. (A) Draining PLNs were harvested from a mouse 1 h after intracutaneous injection of 125I-MCP-1. Sections were stained with anti-PNAd mAb MECA-79 (red) and hematoxylin (blue) and used to generate autoradiographs to localize radiolabeled chemokine (visible as dark grains). (B and C) Intravital micrographs of a draining PLN in an anesthetized mouse ∼1 h after intracutaneous injection of hMCP-1ALEXA. (B) Fluorescent MCP-1 was observed only in HEVs, but not in arterioles (art), whereas (C) the plasma marker FITC-dextran (150 kD) filled the entire microvasculature.
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fig4: MCP-1 accumulates in HEVs after intracutaneous injection. (A) Draining PLNs were harvested from a mouse 1 h after intracutaneous injection of 125I-MCP-1. Sections were stained with anti-PNAd mAb MECA-79 (red) and hematoxylin (blue) and used to generate autoradiographs to localize radiolabeled chemokine (visible as dark grains). (B and C) Intravital micrographs of a draining PLN in an anesthetized mouse ∼1 h after intracutaneous injection of hMCP-1ALEXA. (B) Fluorescent MCP-1 was observed only in HEVs, but not in arterioles (art), whereas (C) the plasma marker FITC-dextran (150 kD) filled the entire microvasculature.

Mentions: While these results established that MCP-1, like other chemokines, is transported from the periphery to draining PLNs, it remained to be determined whether MCP-1 is targeted to HEVs. Two approaches were taken to address this question: first, using autoradiography and immunohistochemistry of draining PLNs, we observed that intracutaneously injected 125I-labeled human MCP-1 was highly concentrated in MECA-79+ HEV (Fig. 4 A); second, using intravital fluorescence microscopy of subiliac PLNs in mice that were injected 40 min earlier with fluorescent hMCP-1ALEXA, we detected hMCP-1ALEXA exclusively in HEVs, but not in arterioles or capillaries (Fig. 4 B and C).


Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues.

Palframan RT, Jung S, Cheng G, Weninger W, Luo Y, Dorf M, Littman DR, Rollins BJ, Zweerink H, Rot A, von Andrian UH - J. Exp. Med. (2001)

MCP-1 accumulates in HEVs after intracutaneous injection. (A) Draining PLNs were harvested from a mouse 1 h after intracutaneous injection of 125I-MCP-1. Sections were stained with anti-PNAd mAb MECA-79 (red) and hematoxylin (blue) and used to generate autoradiographs to localize radiolabeled chemokine (visible as dark grains). (B and C) Intravital micrographs of a draining PLN in an anesthetized mouse ∼1 h after intracutaneous injection of hMCP-1ALEXA. (B) Fluorescent MCP-1 was observed only in HEVs, but not in arterioles (art), whereas (C) the plasma marker FITC-dextran (150 kD) filled the entire microvasculature.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195988&req=5

fig4: MCP-1 accumulates in HEVs after intracutaneous injection. (A) Draining PLNs were harvested from a mouse 1 h after intracutaneous injection of 125I-MCP-1. Sections were stained with anti-PNAd mAb MECA-79 (red) and hematoxylin (blue) and used to generate autoradiographs to localize radiolabeled chemokine (visible as dark grains). (B and C) Intravital micrographs of a draining PLN in an anesthetized mouse ∼1 h after intracutaneous injection of hMCP-1ALEXA. (B) Fluorescent MCP-1 was observed only in HEVs, but not in arterioles (art), whereas (C) the plasma marker FITC-dextran (150 kD) filled the entire microvasculature.
Mentions: While these results established that MCP-1, like other chemokines, is transported from the periphery to draining PLNs, it remained to be determined whether MCP-1 is targeted to HEVs. Two approaches were taken to address this question: first, using autoradiography and immunohistochemistry of draining PLNs, we observed that intracutaneously injected 125I-labeled human MCP-1 was highly concentrated in MECA-79+ HEV (Fig. 4 A); second, using intravital fluorescence microscopy of subiliac PLNs in mice that were injected 40 min earlier with fluorescent hMCP-1ALEXA, we detected hMCP-1ALEXA exclusively in HEVs, but not in arterioles or capillaries (Fig. 4 B and C).

Bottom Line: MCP-1 mRNA in inflamed skin was over 100-fold upregulated and paralleled MCP-1 protein levels, whereas in draining LNs MCP-1 mRNA induction was much weaker and occurred only after a pronounced rise in MCP-1 protein.Thus, MCP-1 in draining LNs was primarily derived from inflamed skin.These findings demonstrate that inflamed peripheral tissues project their local chemokine profile to HEVs in draining LNs and thereby exert "remote control" over the composition of leukocyte populations that home to these organs from the blood.

View Article: PubMed Central - PubMed

Affiliation: Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
Interstitial fluid is constantly drained into lymph nodes (LNs) via afferent lymph vessels. This conduit enables monocyte-derived macrophages and dendritic cells to access LNs from peripheral tissues. We show that during inflammation in the skin, a second recruitment pathway is evoked that recruits large numbers of blood-borne monocytes to LNs via high endothelial venules (HEVs). Inhibition of monocyte chemoattractant protein (MCP)-1 blocked this inflammation-induced monocyte homing to LNs. MCP-1 mRNA in inflamed skin was over 100-fold upregulated and paralleled MCP-1 protein levels, whereas in draining LNs MCP-1 mRNA induction was much weaker and occurred only after a pronounced rise in MCP-1 protein. Thus, MCP-1 in draining LNs was primarily derived from inflamed skin. In MCP-1(-/-) mice, intracutaneously injected MCP-1 accumulated rapidly in the draining LNs where it enhanced monocyte recruitment. Intravital microscopy showed that skin-derived MCP-1 was transported via the lymph to the luminal surface of HEVs where it triggered integrin-dependent arrest of rolling monocytes. These findings demonstrate that inflamed peripheral tissues project their local chemokine profile to HEVs in draining LNs and thereby exert "remote control" over the composition of leukocyte populations that home to these organs from the blood.

Show MeSH
Related in: MedlinePlus