Macrophage network dynamics depend on haptokinesis for optimal local surveillance
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Curated by eLife
Evaluation Summary:
The role of integrins in macrophage function in tissues is not well understood. Using conditional knockout mice with defective integrin (beta1 and beta2) or talin expression, the authors determine that beta1 integrins and talon are each required for normal morphology and efferocytosis by tissue macrophages. This contrasts with chemotaxis in a 3D environments, which is intact in the absence of integrins, as found for dendritic cells and neutrophils. This is an important finding as it established a molecular mechanism for functional integration of macrophages in diverse tissue microenvironments.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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- Immunology and Inflammation (eLife)
Abstract
Macrophages are key immune cells with important roles for tissue surveillance in almost all mammalian organs. Cellular networks made up of many individual macrophages allow for optimal removal of dead cell material and pathogens in tissues. However, the critical determinants that underlie these population responses have not been systematically studied. Here, we investigated how cell shape and the motility of individual cells influences macrophage network responses in 3D culture settings and in mouse tissues. We show that surveying macrophage populations can tolerate lowered actomyosin contractility, but cannot easily compensate for a lack of integrin-mediated adhesion. Although integrins were dispensable for macrophage chemotactic responses, they were crucial to control cell movement and protrusiveness for optimal surveillance by a macrophage population. Our study reveals that β1 integrins are important for maintaining macrophage shape and network sampling efficiency in mammalian tissues, and sets macrophage motility strategies apart from the integrin-independent 3D migration modes of many other immune cell subsets.
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Evaluation Summary:
The role of integrins in macrophage function in tissues is not well understood. Using conditional knockout mice with defective integrin (beta1 and beta2) or talin expression, the authors determine that beta1 integrins and talon are each required for normal morphology and efferocytosis by tissue macrophages. This contrasts with chemotaxis in a 3D environments, which is intact in the absence of integrins, as found for dendritic cells and neutrophils. This is an important finding as it established a molecular mechanism for functional integration of macrophages in diverse tissue microenvironments.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with …
Evaluation Summary:
The role of integrins in macrophage function in tissues is not well understood. Using conditional knockout mice with defective integrin (beta1 and beta2) or talin expression, the authors determine that beta1 integrins and talon are each required for normal morphology and efferocytosis by tissue macrophages. This contrasts with chemotaxis in a 3D environments, which is intact in the absence of integrins, as found for dendritic cells and neutrophils. This is an important finding as it established a molecular mechanism for functional integration of macrophages in diverse tissue microenvironments.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The authors have set out to define the role of integrins in macrophage function using in vitro and in vivo analysis and conditional/inducible knockout mice. The authors use in vitro systems to investigate chemotaxis in a 3D environment, an in vitro model for efferocytosis based on phosphatidylserine coated beads, and in vivo investigation of efficient efferocytosis in lymph nodes. The authors have demonstrate that macrophages can chemotax in a 3D collagen gel without integrins, although the WT and KO cells are slower than dendritic cells or neutrophils. Integrins were similar not required for macrophages to move towards find me signals generated by laser injury. However, profound morphological changes and defects in efferocytosis are noted in vitro and in vivo. The in vivo system shows that defect in …
Reviewer #1 (Public Review):
The authors have set out to define the role of integrins in macrophage function using in vitro and in vivo analysis and conditional/inducible knockout mice. The authors use in vitro systems to investigate chemotaxis in a 3D environment, an in vitro model for efferocytosis based on phosphatidylserine coated beads, and in vivo investigation of efficient efferocytosis in lymph nodes. The authors have demonstrate that macrophages can chemotax in a 3D collagen gel without integrins, although the WT and KO cells are slower than dendritic cells or neutrophils. Integrins were similar not required for macrophages to move towards find me signals generated by laser injury. However, profound morphological changes and defects in efferocytosis are noted in vitro and in vivo. The in vivo system shows that defect in haptokinesis based largely on beta1 integrin function are responsible for the efferocytosis defect in vitro. As macrophages are tissue resident cells that often display a "mesenchymal" like morphology and play an important homeostatic role in clearance of apoptotic cells the demonstration of a clear and selective role of integrins in these processes is biologically important.
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Reviewer #2 (Public Review):
In this study, the authors use live imaging and both in vitro and in vivo approaches to investigate how a lack of integrin function affects macrophage motility and how these highly adaptive cells can compensate for a loss of adhesiveness within a complex three dimensional environment. They also investigate how the shape and mode of motility used by an individual cell can influence the efferocytic ability of a macrophage. This is a fascinating question and builds on recent evidence that macrophages have evolved mechanisms to ensure efficient efferocytosis within the many different environments in which a they find themselves in vivo. The imaging is excellent and the data of high quality. However, not all the conclusions are supported by the experimental results in their current format and alternative …
Reviewer #2 (Public Review):
In this study, the authors use live imaging and both in vitro and in vivo approaches to investigate how a lack of integrin function affects macrophage motility and how these highly adaptive cells can compensate for a loss of adhesiveness within a complex three dimensional environment. They also investigate how the shape and mode of motility used by an individual cell can influence the efferocytic ability of a macrophage. This is a fascinating question and builds on recent evidence that macrophages have evolved mechanisms to ensure efficient efferocytosis within the many different environments in which a they find themselves in vivo. The imaging is excellent and the data of high quality. However, not all the conclusions are supported by the experimental results in their current format and alternative interpretations cannot be ruled out.
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Reviewer #3 (Public Review):
In this study, Paterson and Lämmermann examine the molecular basis underlying the scanning and efferocytic behavior of tissue macrophages. In fact, while efferocytosis is central for tissue homeostasis, there has been thus far a surprising lack of information on the strategies employed by macrophages during this process. Using an elegant combination of in vitro/in vitro imaging, as well as genetic and pharmacological manipulation of macrophages, the authors uncover a central role for the beta1 - talin signaling axis to promote haptotactic motility and clearance of apoptotic bodies. This is in contrast to the largely integrin-independent motility shown by dendritic cells and other leukocytes. The authors further report that macrophages display some flexibility in their efferocytosis strategies, by regulating …
Reviewer #3 (Public Review):
In this study, Paterson and Lämmermann examine the molecular basis underlying the scanning and efferocytic behavior of tissue macrophages. In fact, while efferocytosis is central for tissue homeostasis, there has been thus far a surprising lack of information on the strategies employed by macrophages during this process. Using an elegant combination of in vitro/in vitro imaging, as well as genetic and pharmacological manipulation of macrophages, the authors uncover a central role for the beta1 - talin signaling axis to promote haptotactic motility and clearance of apoptotic bodies. This is in contrast to the largely integrin-independent motility shown by dendritic cells and other leukocytes. The authors further report that macrophages display some flexibility in their efferocytosis strategies, by regulating either baseline motility or via extension of long protrusions.
Altogether, the work performed by the authors is comprehensive, complete and elegantly presented, and the data interpretation is consistent with the results.
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