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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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Neutrophils migrate away from one  chemoattractant source towards another. (a) Photographs of stained neutrophils after 2-h migration  towards a distant source of  LTB4 or IL-8 (1 pmol), in  the presence or absence of an  inverse gradient generated  by LTB4 or IL-8 (10 pmol).  Cells placed with one agonist migrate towards the  other agonist almost as well  as control cells, but do not  migrate well towards a distant source of the same agonist. (b) Dose-response  curves illustrate that over a  wide range of concentrations  of both agonists, cells can migrate away from an IL-8  source in response to a target  LTB4 gradient; however,  cells do not migrate away  from a well containing IL-8  (⩾1 pmol) towards a distant  IL-8 source. (c) Conversely,  over a wide concentration  range of close and distant agonists, neutrophils migrate  away from an LTB4 source  towards IL-8, but not towards LTB4. Each graph in b  and c shows the data from a  representative experiment  of at least two to five performed with similar results.  Error bars in b and c indicate  the standard deviation of the  distance migrated for four  replicates.
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Figure 1: Neutrophils migrate away from one chemoattractant source towards another. (a) Photographs of stained neutrophils after 2-h migration towards a distant source of LTB4 or IL-8 (1 pmol), in the presence or absence of an inverse gradient generated by LTB4 or IL-8 (10 pmol). Cells placed with one agonist migrate towards the other agonist almost as well as control cells, but do not migrate well towards a distant source of the same agonist. (b) Dose-response curves illustrate that over a wide range of concentrations of both agonists, cells can migrate away from an IL-8 source in response to a target LTB4 gradient; however, cells do not migrate away from a well containing IL-8 (⩾1 pmol) towards a distant IL-8 source. (c) Conversely, over a wide concentration range of close and distant agonists, neutrophils migrate away from an LTB4 source towards IL-8, but not towards LTB4. Each graph in b and c shows the data from a representative experiment of at least two to five performed with similar results. Error bars in b and c indicate the standard deviation of the distance migrated for four replicates.

Mentions: Given the multiple cell types that produce leukocyte chemoattractants, leukocytes responding to a distant attractant from a target site may often be faced with the dilemma of having to migrate away from a local agonist source to reach their destination. To model this situation in the under-agarose assay, we placed neutrophils together with various concentrations of a primary agonist in one well (well 1), and assessed their ability to migrate away from the primary source towards a distant source of the same or of a different chemoattractant (in well 2). Addition of IL-8 to the well containing neutrophils efficiently inhibited chemotaxis towards a distant IL-8 source, as expected (Fig. 1, a and b). In contrast, addition of LTB4 to the cell well had little or no effect on migration to IL-8; only at the highest LTB4 doses was there a minimal effect on the distance of neutrophil migration to IL-8 (Fig. 1, a and b). Similarly, placing LTB4 with cells in well 1 inhibited migration to a distant LTB4 source (well 2), but neutrophils migrated efficiently away from a local IL-8 source towards the distant lipid attractant (Fig. 1, a and c). Thus neutrophils can readily migrate from a well containing a primary agonist towards a distant secondary attractant well.


Multistep navigation and the combinatorial control of leukocyte chemotaxis.

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

Neutrophils migrate away from one  chemoattractant source towards another. (a) Photographs of stained neutrophils after 2-h migration  towards a distant source of  LTB4 or IL-8 (1 pmol), in  the presence or absence of an  inverse gradient generated  by LTB4 or IL-8 (10 pmol).  Cells placed with one agonist migrate towards the  other agonist almost as well  as control cells, but do not  migrate well towards a distant source of the same agonist. (b) Dose-response  curves illustrate that over a  wide range of concentrations  of both agonists, cells can migrate away from an IL-8  source in response to a target  LTB4 gradient; however,  cells do not migrate away  from a well containing IL-8  (⩾1 pmol) towards a distant  IL-8 source. (c) Conversely,  over a wide concentration  range of close and distant agonists, neutrophils migrate  away from an LTB4 source  towards IL-8, but not towards LTB4. Each graph in b  and c shows the data from a  representative experiment  of at least two to five performed with similar results.  Error bars in b and c indicate  the standard deviation of the  distance migrated for four  replicates.
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Related In: Results  -  Collection

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Figure 1: Neutrophils migrate away from one chemoattractant source towards another. (a) Photographs of stained neutrophils after 2-h migration towards a distant source of LTB4 or IL-8 (1 pmol), in the presence or absence of an inverse gradient generated by LTB4 or IL-8 (10 pmol). Cells placed with one agonist migrate towards the other agonist almost as well as control cells, but do not migrate well towards a distant source of the same agonist. (b) Dose-response curves illustrate that over a wide range of concentrations of both agonists, cells can migrate away from an IL-8 source in response to a target LTB4 gradient; however, cells do not migrate away from a well containing IL-8 (⩾1 pmol) towards a distant IL-8 source. (c) Conversely, over a wide concentration range of close and distant agonists, neutrophils migrate away from an LTB4 source towards IL-8, but not towards LTB4. Each graph in b and c shows the data from a representative experiment of at least two to five performed with similar results. Error bars in b and c indicate the standard deviation of the distance migrated for four replicates.
Mentions: Given the multiple cell types that produce leukocyte chemoattractants, leukocytes responding to a distant attractant from a target site may often be faced with the dilemma of having to migrate away from a local agonist source to reach their destination. To model this situation in the under-agarose assay, we placed neutrophils together with various concentrations of a primary agonist in one well (well 1), and assessed their ability to migrate away from the primary source towards a distant source of the same or of a different chemoattractant (in well 2). Addition of IL-8 to the well containing neutrophils efficiently inhibited chemotaxis towards a distant IL-8 source, as expected (Fig. 1, a and b). In contrast, addition of LTB4 to the cell well had little or no effect on migration to IL-8; only at the highest LTB4 doses was there a minimal effect on the distance of neutrophil migration to IL-8 (Fig. 1, a and b). Similarly, placing LTB4 with cells in well 1 inhibited migration to a distant LTB4 source (well 2), but neutrophils migrated efficiently away from a local IL-8 source towards the distant lipid attractant (Fig. 1, a and c). Thus neutrophils can readily migrate from a well containing a primary agonist towards a distant secondary attractant well.

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