Integrins are Mechanosensors That Modulate Human Eosinophil Activation

Area of Science:

• Immunology
• Cell Biology
• Biophysics

Background:

• Eosinophil lung migration is controlled by eotaxins, which affect intracellular calcium (Ca(2+)) and cell function.
• Eosinophil responses are also influenced by mechanical forces (flow-dependent), but the underlying molecular mechanisms are unclear.

Purpose of the Study:

• To investigate the effects of fluid shear stress on intracellular calcium concentration ([Ca(2+)]i) in human peripheral blood eosinophils.
• To identify the molecular mechanosensor responsible for flow-induced eosinophil responses.

Main Methods:

• Confocal fluorescence microscopy was used to observe [Ca(2+)]i changes in eosinophils under fluid shear stress.
• Cells were perfused in a parallel-plate flow chamber, with and without eotaxin-1 stimulation.
• Integrin receptor antagonists (CDP-323, RGD tripeptides) and intracellular calcium chelators (BAPTA) were used to probe the mechanisms.

Main Results:

• Fluid perfusion induced a calcium response (PICR) leading to eosinophil flattening, increased cell area, shape change, and non-directional migration.
• These flow-induced changes were abolished by BAPTA, indicating Ca(2+) dependence.
• Eotaxin-1 enhanced the flow-induced responses.
• PICR was blocked by integrin antagonists, implicating α4β7/α4β1 integrins in mediating the response.

Conclusions:

• Fluid shear stress activates human eosinophils via a Ca(2+)-dependent mechanism involving integrin receptors.
• This study provides the first pharmacological description of a molecular mechanosensor in eosinophils.
• This mechanosensor may cooperate with eotaxin-1 signaling to regulate eosinophil activation and migration.