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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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Monocytes home to inflamed PLNs via HEVs. Adoptive transfer of CX3CR1+/GFP PBMCs into wild-type recipients was performed 5 d after induction of skin inflammation as described in Fig. 2. Draining PLNs were removed after 1 h and prepared for confocal microscopy using appropriate filters for detection of GFP+ monocytes (green) and HEVs, which were visualized using anti-PNAd mAb MECA-79 and Cy5-labeled anti–rat IgM (red). (A) Representative confocal micrographs of homed GFP+ monocytes in close proximity to MECA-79+ HEVs. (B) The frequency distribution of homed GFP+ monocytes relative to MECA-79+ HEVs and the subcapsular sinus was determined. Data are expressed as mean ± SEM of the percentage of GFP+ cells in each class. n = 90 random sections of five inflamed PLNs from two independent experiments.
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fig3: Monocytes home to inflamed PLNs via HEVs. Adoptive transfer of CX3CR1+/GFP PBMCs into wild-type recipients was performed 5 d after induction of skin inflammation as described in Fig. 2. Draining PLNs were removed after 1 h and prepared for confocal microscopy using appropriate filters for detection of GFP+ monocytes (green) and HEVs, which were visualized using anti-PNAd mAb MECA-79 and Cy5-labeled anti–rat IgM (red). (A) Representative confocal micrographs of homed GFP+ monocytes in close proximity to MECA-79+ HEVs. (B) The frequency distribution of homed GFP+ monocytes relative to MECA-79+ HEVs and the subcapsular sinus was determined. Data are expressed as mean ± SEM of the percentage of GFP+ cells in each class. n = 90 random sections of five inflamed PLNs from two independent experiments.

Mentions: To determine the route by which monocytes entered PLNs, we removed inflamed subiliac PLNs from recipients 60 min after injecting CX3CR1+/GFP PBMC either intravenously or directly into the inflamed flank skin. Cryosections were stained with anti-PNAd mAb MECA-79 to identify HEVs, and the position of GFP+ monocytes within the PLN was analyzed by confocal microscopy (Fig. 3 A). When CX3CR+/GFP cells were injected intracutaneously 1 h before tissue harvest, no GFP+ cells could be found in multiple sections of draining PLNs suggesting that, during this relatively short time interval, monocytes do not enter afferent lymphatics in substantial numbers (data not shown). In contrast, after intravenous injection, numerous GFP+ cells were found in inflamed PLNs. The vast majority of these cells was associated with HEVs, with 31% of GFP+ leukocytes found either within the lumen or the vessel wall (Fig. 3 B) and 51% located in the T cell area within 5 cell diameters (<40 μm) of the closest HEV. Only 3% of all GFP+ leukocytes were found in the subcapsular sinus, the site of entry for leukocytes in afferent lymph. This HEV-centric distribution of monocytes in PLNs was remarkably similar to that of naive T cells (unpublished data), which are known to access PLNs exclusively via HEVs (6–8). We conclude that at least within the first hour after adoptive transfer monocytes enter inflamed PLNs preferentially via HEVs and not via afferent lymph vessels.


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)

Monocytes home to inflamed PLNs via HEVs. Adoptive transfer of CX3CR1+/GFP PBMCs into wild-type recipients was performed 5 d after induction of skin inflammation as described in Fig. 2. Draining PLNs were removed after 1 h and prepared for confocal microscopy using appropriate filters for detection of GFP+ monocytes (green) and HEVs, which were visualized using anti-PNAd mAb MECA-79 and Cy5-labeled anti–rat IgM (red). (A) Representative confocal micrographs of homed GFP+ monocytes in close proximity to MECA-79+ HEVs. (B) The frequency distribution of homed GFP+ monocytes relative to MECA-79+ HEVs and the subcapsular sinus was determined. Data are expressed as mean ± SEM of the percentage of GFP+ cells in each class. n = 90 random sections of five inflamed PLNs from two independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195988&req=5

fig3: Monocytes home to inflamed PLNs via HEVs. Adoptive transfer of CX3CR1+/GFP PBMCs into wild-type recipients was performed 5 d after induction of skin inflammation as described in Fig. 2. Draining PLNs were removed after 1 h and prepared for confocal microscopy using appropriate filters for detection of GFP+ monocytes (green) and HEVs, which were visualized using anti-PNAd mAb MECA-79 and Cy5-labeled anti–rat IgM (red). (A) Representative confocal micrographs of homed GFP+ monocytes in close proximity to MECA-79+ HEVs. (B) The frequency distribution of homed GFP+ monocytes relative to MECA-79+ HEVs and the subcapsular sinus was determined. Data are expressed as mean ± SEM of the percentage of GFP+ cells in each class. n = 90 random sections of five inflamed PLNs from two independent experiments.
Mentions: To determine the route by which monocytes entered PLNs, we removed inflamed subiliac PLNs from recipients 60 min after injecting CX3CR1+/GFP PBMC either intravenously or directly into the inflamed flank skin. Cryosections were stained with anti-PNAd mAb MECA-79 to identify HEVs, and the position of GFP+ monocytes within the PLN was analyzed by confocal microscopy (Fig. 3 A). When CX3CR+/GFP cells were injected intracutaneously 1 h before tissue harvest, no GFP+ cells could be found in multiple sections of draining PLNs suggesting that, during this relatively short time interval, monocytes do not enter afferent lymphatics in substantial numbers (data not shown). In contrast, after intravenous injection, numerous GFP+ cells were found in inflamed PLNs. The vast majority of these cells was associated with HEVs, with 31% of GFP+ leukocytes found either within the lumen or the vessel wall (Fig. 3 B) and 51% located in the T cell area within 5 cell diameters (<40 μm) of the closest HEV. Only 3% of all GFP+ leukocytes were found in the subcapsular sinus, the site of entry for leukocytes in afferent lymph. This HEV-centric distribution of monocytes in PLNs was remarkably similar to that of naive T cells (unpublished data), which are known to access PLNs exclusively via HEVs (6–8). We conclude that at least within the first hour after adoptive transfer monocytes enter inflamed PLNs preferentially via HEVs and not via afferent lymph vessels.

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