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Multistep navigation and the combinatorial control of leukocyte chemotaxis.

Foxman EF, Campbell JJ, Butcher EC - J. Cell Biol. (1997)

Bottom Line: Furthermore, cells can chemotax effectively to a secondary distant agonist after migrating up a primary gradient into a saturating, nonorienting concentration of an initial attractant.Together, these observations suggest the potential for cells' step-by-step navigation from one gradient to another in complex chemoattractant fields.We propose a multistep model of chemoattractant-directed migration, which requires that leukocytes display multiple chemoattractant receptors for successful homing and provides for combinatorial determination of microenvironmental localization.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, and the Digestive Disease Center, Department of Medicine, Stanford University Medical School, Stanford, California 94305-5324, USA.

ABSTRACT
Cells migrating within tissues may encounter multiple chemoattractant signals in complex spatial and temporal patterns. To understand leukocyte navigation in such settings, we have explored the migratory behavior of neutrophils in model scenarios where they are presented with two chemoattractant sources in various configurations. We show that, over a wide range of conditions, neutrophils can migrate "down" a local chemoattractant gradient in response to a distant gradient of a different chemoattractant. Furthermore, cells can chemotax effectively to a secondary distant agonist after migrating up a primary gradient into a saturating, nonorienting concentration of an initial attractant. Together, these observations suggest the potential for cells' step-by-step navigation from one gradient to another in complex chemoattractant fields. The importance of such sequential navigation is confirmed here in a model system in which neutrophil homing to a defined domain (a) requires serial responses to agonists presented in a defined spatial array, and (b) is a function of both the agonist combination and the sequence in which gradients are encountered. We propose a multistep model of chemoattractant-directed migration, which requires that leukocytes display multiple chemoattractant receptors for successful homing and provides for combinatorial determination of microenvironmental localization.

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The migratory behavior of cells originating at  a source of fMLP or C5a. (a)  Photographs of stained cells  after 2-h migration to a source  of fMLP, IL-8, or LTB4 (1  pmol). Cells originating in a  well containing IL-8 or LTB4  (10 pmol) exhibit robust migration towards fMLP (top  row); however, cells placed  with fMLP (10 pmol) do not  migrate towards IL-8 or LTB4.  (b) Dose-response curves  show the effect of varying  concentrations of fMLP and  C5a on migration to IL-8 and  LTB4, and the effect of varying amounts of IL-8 and  LTB4 on migration to fMLP  and C5a. Each graph shows  the data from a representative experiment of two to five  performed with similar results; error bars indicate the  standard deviation of the distance migrated for four replicates.
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Figure 4: The migratory behavior of cells originating at a source of fMLP or C5a. (a) Photographs of stained cells after 2-h migration to a source of fMLP, IL-8, or LTB4 (1 pmol). Cells originating in a well containing IL-8 or LTB4 (10 pmol) exhibit robust migration towards fMLP (top row); however, cells placed with fMLP (10 pmol) do not migrate towards IL-8 or LTB4. (b) Dose-response curves show the effect of varying concentrations of fMLP and C5a on migration to IL-8 and LTB4, and the effect of varying amounts of IL-8 and LTB4 on migration to fMLP and C5a. Each graph shows the data from a representative experiment of two to five performed with similar results; error bars indicate the standard deviation of the distance migrated for four replicates.

Mentions: The cells' ability to ignore a local agonist source to respond to a distant one is constrained by the dominance of end target–derived attractants (N-formyl peptide fMet-Leu-Phe [fMLP], C5a) over regulatory cell–derived attractants (IL-8, LTB4), in a manner consistent with previous studies in other model systems (4, 6, 12). Whereas neutrophils could migrate away from a local IL-8 or LTB4 source towards fMLP or C5a (Fig. 4, a and b), cells originating from a high local concentration of fMLP or C5a do not respond efficiently to a distant source of IL-8 or LTB4. Local fMLP also suppressed migration to a distant source of C5a and, although less completely, C5a also suppressed migration to fMLP (data not shown).


Multistep navigation and the combinatorial control of leukocyte chemotaxis.

Foxman EF, Campbell JJ, Butcher EC - J. Cell Biol. (1997)

The migratory behavior of cells originating at  a source of fMLP or C5a. (a)  Photographs of stained cells  after 2-h migration to a source  of fMLP, IL-8, or LTB4 (1  pmol). Cells originating in a  well containing IL-8 or LTB4  (10 pmol) exhibit robust migration towards fMLP (top  row); however, cells placed  with fMLP (10 pmol) do not  migrate towards IL-8 or LTB4.  (b) Dose-response curves  show the effect of varying  concentrations of fMLP and  C5a on migration to IL-8 and  LTB4, and the effect of varying amounts of IL-8 and  LTB4 on migration to fMLP  and C5a. Each graph shows  the data from a representative experiment of two to five  performed with similar results; error bars indicate the  standard deviation of the distance migrated for four replicates.
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Related In: Results  -  Collection

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Figure 4: The migratory behavior of cells originating at a source of fMLP or C5a. (a) Photographs of stained cells after 2-h migration to a source of fMLP, IL-8, or LTB4 (1 pmol). Cells originating in a well containing IL-8 or LTB4 (10 pmol) exhibit robust migration towards fMLP (top row); however, cells placed with fMLP (10 pmol) do not migrate towards IL-8 or LTB4. (b) Dose-response curves show the effect of varying concentrations of fMLP and C5a on migration to IL-8 and LTB4, and the effect of varying amounts of IL-8 and LTB4 on migration to fMLP and C5a. Each graph shows the data from a representative experiment of two to five performed with similar results; error bars indicate the standard deviation of the distance migrated for four replicates.
Mentions: The cells' ability to ignore a local agonist source to respond to a distant one is constrained by the dominance of end target–derived attractants (N-formyl peptide fMet-Leu-Phe [fMLP], C5a) over regulatory cell–derived attractants (IL-8, LTB4), in a manner consistent with previous studies in other model systems (4, 6, 12). Whereas neutrophils could migrate away from a local IL-8 or LTB4 source towards fMLP or C5a (Fig. 4, a and b), cells originating from a high local concentration of fMLP or C5a do not respond efficiently to a distant source of IL-8 or LTB4. Local fMLP also suppressed migration to a distant source of C5a and, although less completely, C5a also suppressed migration to fMLP (data not shown).

Bottom Line: Furthermore, cells can chemotax effectively to a secondary distant agonist after migrating up a primary gradient into a saturating, nonorienting concentration of an initial attractant.Together, these observations suggest the potential for cells' step-by-step navigation from one gradient to another in complex chemoattractant fields.We propose a multistep model of chemoattractant-directed migration, which requires that leukocytes display multiple chemoattractant receptors for successful homing and provides for combinatorial determination of microenvironmental localization.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunology and Vascular Biology, Department of Pathology, and the Digestive Disease Center, Department of Medicine, Stanford University Medical School, Stanford, California 94305-5324, USA.

ABSTRACT
Cells migrating within tissues may encounter multiple chemoattractant signals in complex spatial and temporal patterns. To understand leukocyte navigation in such settings, we have explored the migratory behavior of neutrophils in model scenarios where they are presented with two chemoattractant sources in various configurations. We show that, over a wide range of conditions, neutrophils can migrate "down" a local chemoattractant gradient in response to a distant gradient of a different chemoattractant. Furthermore, cells can chemotax effectively to a secondary distant agonist after migrating up a primary gradient into a saturating, nonorienting concentration of an initial attractant. Together, these observations suggest the potential for cells' step-by-step navigation from one gradient to another in complex chemoattractant fields. The importance of such sequential navigation is confirmed here in a model system in which neutrophil homing to a defined domain (a) requires serial responses to agonists presented in a defined spatial array, and (b) is a function of both the agonist combination and the sequence in which gradients are encountered. We propose a multistep model of chemoattractant-directed migration, which requires that leukocytes display multiple chemoattractant receptors for successful homing and provides for combinatorial determination of microenvironmental localization.

Show MeSH
Related in: MedlinePlus