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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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MCP-1 triggers the arrest of rolling monocytes in PLN HEVs. Adhesive behavior of WEHI78/24 cells in venular trees of subiliac PLNs was analyzed by intravital microscopy. Experiments were performed in wild-type mice draining either normal (white bars) or inflamed skin (black bars) and in inflamed PLNs of MCP-1−/− mice that were either untreated (hatched bars) or injected intracutaneously with MCP-1 (cross-hatched bars). Rolling fractions (percentage of total cells passing through a given venule which interact with the vessel wall) and sticking fractions (percentage of rolling cells which arrest for ≥30 s) are shown in each branching order of the venular tree (A and C) and as the mean for all venules (B and D). Mean ± SEM; total number of animals/venules analyzed are shown in B and D. (E) Desensitization of WEHI78/24 cells to MCP-1, but not MIP-1α inhibits arrest in inflamed PLN HEVs. WEHI78/24 cells were incubated for 40 min with MIP-1α (500 nM) or MCP-1 (500 nM). Desensitized WEHI78/24 cells were injected into MCP-1−/− mice, which had been pretreated 7 d and 40 min earlier with intracutaneous injections of CFA/KLH and 100 pmol MCP-1, respectively. Mean rolling and sticking fractions in 21 HEVs (13 order IV and 8 order V) in three mice are shown for each group. **P < 0.01.
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fig6: MCP-1 triggers the arrest of rolling monocytes in PLN HEVs. Adhesive behavior of WEHI78/24 cells in venular trees of subiliac PLNs was analyzed by intravital microscopy. Experiments were performed in wild-type mice draining either normal (white bars) or inflamed skin (black bars) and in inflamed PLNs of MCP-1−/− mice that were either untreated (hatched bars) or injected intracutaneously with MCP-1 (cross-hatched bars). Rolling fractions (percentage of total cells passing through a given venule which interact with the vessel wall) and sticking fractions (percentage of rolling cells which arrest for ≥30 s) are shown in each branching order of the venular tree (A and C) and as the mean for all venules (B and D). Mean ± SEM; total number of animals/venules analyzed are shown in B and D. (E) Desensitization of WEHI78/24 cells to MCP-1, but not MIP-1α inhibits arrest in inflamed PLN HEVs. WEHI78/24 cells were incubated for 40 min with MIP-1α (500 nM) or MCP-1 (500 nM). Desensitized WEHI78/24 cells were injected into MCP-1−/− mice, which had been pretreated 7 d and 40 min earlier with intracutaneous injections of CFA/KLH and 100 pmol MCP-1, respectively. Mean rolling and sticking fractions in 21 HEVs (13 order IV and 8 order V) in three mice are shown for each group. **P < 0.01.

Mentions: Rolling fractions of WEHI78/24 monocytes were similar in inflamed and resting PLNs of both wild-type and MCP-1−/− mice (Fig. 6 A and B). However, rolling WEHI78/24 cells arrested significantly more frequently in inflamed PLNs of wild-type mice compared with noninflamed wild-type PLNs or inflamed PLNs in MCP-1−/− mice (Fig. 6 C and D). Both rolling and sticking was more frequent in paracortical high order branches of the venular tree (Fig. 6 A and C), as shown previously for lymphocytes (21, 29). Importantly, injection of MCP-1 into inflamed skin of MCP-1−/− mice restored the ability of rolling monocytes to stick in high order HEVs of the draining PLN.


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 triggers the arrest of rolling monocytes in PLN HEVs. Adhesive behavior of WEHI78/24 cells in venular trees of subiliac PLNs was analyzed by intravital microscopy. Experiments were performed in wild-type mice draining either normal (white bars) or inflamed skin (black bars) and in inflamed PLNs of MCP-1−/− mice that were either untreated (hatched bars) or injected intracutaneously with MCP-1 (cross-hatched bars). Rolling fractions (percentage of total cells passing through a given venule which interact with the vessel wall) and sticking fractions (percentage of rolling cells which arrest for ≥30 s) are shown in each branching order of the venular tree (A and C) and as the mean for all venules (B and D). Mean ± SEM; total number of animals/venules analyzed are shown in B and D. (E) Desensitization of WEHI78/24 cells to MCP-1, but not MIP-1α inhibits arrest in inflamed PLN HEVs. WEHI78/24 cells were incubated for 40 min with MIP-1α (500 nM) or MCP-1 (500 nM). Desensitized WEHI78/24 cells were injected into MCP-1−/− mice, which had been pretreated 7 d and 40 min earlier with intracutaneous injections of CFA/KLH and 100 pmol MCP-1, respectively. Mean rolling and sticking fractions in 21 HEVs (13 order IV and 8 order V) in three mice are shown for each group. **P < 0.01.
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fig6: MCP-1 triggers the arrest of rolling monocytes in PLN HEVs. Adhesive behavior of WEHI78/24 cells in venular trees of subiliac PLNs was analyzed by intravital microscopy. Experiments were performed in wild-type mice draining either normal (white bars) or inflamed skin (black bars) and in inflamed PLNs of MCP-1−/− mice that were either untreated (hatched bars) or injected intracutaneously with MCP-1 (cross-hatched bars). Rolling fractions (percentage of total cells passing through a given venule which interact with the vessel wall) and sticking fractions (percentage of rolling cells which arrest for ≥30 s) are shown in each branching order of the venular tree (A and C) and as the mean for all venules (B and D). Mean ± SEM; total number of animals/venules analyzed are shown in B and D. (E) Desensitization of WEHI78/24 cells to MCP-1, but not MIP-1α inhibits arrest in inflamed PLN HEVs. WEHI78/24 cells were incubated for 40 min with MIP-1α (500 nM) or MCP-1 (500 nM). Desensitized WEHI78/24 cells were injected into MCP-1−/− mice, which had been pretreated 7 d and 40 min earlier with intracutaneous injections of CFA/KLH and 100 pmol MCP-1, respectively. Mean rolling and sticking fractions in 21 HEVs (13 order IV and 8 order V) in three mice are shown for each group. **P < 0.01.
Mentions: Rolling fractions of WEHI78/24 monocytes were similar in inflamed and resting PLNs of both wild-type and MCP-1−/− mice (Fig. 6 A and B). However, rolling WEHI78/24 cells arrested significantly more frequently in inflamed PLNs of wild-type mice compared with noninflamed wild-type PLNs or inflamed PLNs in MCP-1−/− mice (Fig. 6 C and D). Both rolling and sticking was more frequent in paracortical high order branches of the venular tree (Fig. 6 A and C), as shown previously for lymphocytes (21, 29). Importantly, injection of MCP-1 into inflamed skin of MCP-1−/− mice restored the ability of rolling monocytes to stick in high order HEVs of the draining PLN.

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