A Shape Sensing Mechanism driven by Arp2/3 and cPLA<sub>2</sub>licenses Dendritic Cells for Migration to Lymph Nodes in Homeostasis

Alraies, Zahraa; Rivera, Claudia A; Delgado, Maria–Graciela; Sanséau, Doriane; Maurin, Matthieu; Yatim, Aline; Saéz, Pablo; Williart, Alice; Gratia, Matthieu; Silva, Nilushi S. De; Moreau, Aurélie; Albaud, Benoit; Legoix, Patricia; Nakano, Hideki; Cook, Donald N.; Lawrence, Toby; Manel, Nicolas; Moreau, Hélène D.; Nader, Guilherme P.F.; Piel, Matthieu; Lennon-Duménil, Ana-María

doi:10.1101/2022.08.09.503223

Cited by 7 publications

(3 citation statements)

References 112 publications

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“…1k). As cellular confinement between two surfaces is sufficient to trigger a switch in cellular behaviors resembling cellular behaviors in 'true' 3D environments [22][23][24] , these findings suggest that macropinocytosis may be generally enhanced when cells are located within 3D microenvironments. To corroborate these findings, we embedded macrophages into 3D matrices composed of collagen I (Extended Data Movie 1), a typical component of extracellular matrices.…”

Section: D Microenvironments Enhance Macropinocytosismentioning

confidence: 90%

Microenvironmental Regulation of Macropinocytosis Facilitates Extracellular Fluid Sampling

Renkawitz,

Braun,

Reza

et al. 2024

Preprint

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Cells sense chemical and mechanical signals within their local microenvironment. To sample for chemical signals, cells employ bulk extracellular fluid uptake through macropinocytosis in a receptor-independent manner. Although macropinocytosis occurs in microenvironments of multicellular organisms, it remains largely unknown whether and how the microenvironment itself regulates fluid sampling. Here, we reveal that the microenvironmental properties regulate fluid sampling by macropinocytosis. Using macrophages as constitutively sampling immune cells, we discover that macropinocytosis in three-dimensional (3D) microenvironments is more efficient than on flat 2D surfaces. Enhanced macropinocytosis in 3D is driven by low adhesiveness to the cellular substrate, releasing the mechanical linkage between the cell and its surroundings, thereby facilitating the formation of actin-based membrane protrusions that sample the local substrate-free space. Mechanistically, we identify that the microenvironment regulates the utilization of macropinocytosis-competent actin networks, as the actin nucleating Arp2/3 complex and its regulator Hem1 particularly drive macropinocytosis in 3D. Our results establish microenvironmental properties as stimulators and regulators of macropinocytosis, providing important implications for fluid sampling during physiology, immunity, and diseases. Additionally, our findings identify a reciprocal relationship between the microenvironment and fluid sampling, wherein cells acquire information from the microenvironment by macropinocytosis, while this process, in turn, is regulated by the microenvironment.

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Section: D Microenvironments Enhance Macropinocytosismentioning

confidence: 90%

Microenvironmental Regulation of Macropinocytosis Facilitates Extracellular Fluid Sampling

Renkawitz,

Braun,

Reza

et al. 2024

Preprint

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“…To date, the precise factors generating AA and other signals involved in nuclear mechanosensing are not well characterized owing to the complex cell type-specific regulation of lipid metabolism and Ca 2+ channel expression (79)(80)(81). As an example, the cPLA2a isoform, which has been implicated in regulating the contractile response in DCs and zebrafish progenitor stem cells (29,30,82), is absent or only expressed at very low levels in mature T cells. Together with the fact that compensatory mechanisms between different isoforms might occur, genetic approaches to disrupt mechanosensing in T RM constitute a formidable challenge.…”

Section: Discussionmentioning

confidence: 99%

Exocrine gland–resident memory CD8 ⁺ T cells use mechanosensing for tissue surveillance

Ruef,

Martínez Magdaleno,

Ficht

et al. 2023

Sci. Immunol.

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Tissue-resident CD8 + T cells (T RM ) continuously scan peptide-MHC (pMHC) complexes in their organ of residence to intercept microbial invaders. Recent data showed that T RM lodged in exocrine glands scan tissue in the absence of any chemoattractant or adhesion receptor signaling, thus bypassing the requirement for canonical migration-promoting factors. The signals eliciting this noncanonical motility and its relevance for organ surveillance have remained unknown. Using mouse models of viral infections, we report that exocrine gland T RM autonomously generated front-to-back F-actin flow for locomotion, accompanied by high cortical actomyosin contractility, and leading-edge bleb formation. The distinctive mode of exocrine gland T RM locomotion was triggered by sensing physical confinement and was closely correlated with nuclear deformation, which acts as a mechanosensor via an arachidonic acid and Ca 2+ signaling pathway. By contrast, naïve CD8 + T cells or T RM surveilling microbe-exposed epithelial barriers did not show mechanosensing capacity. Inhibition of nuclear mechanosensing disrupted exocrine gland T RM scanning and impaired their ability to intercept target cells. These findings indicate that confinement is sufficient to elicit autonomous T cell surveillance in glands with restricted chemokine expression and constitutes a scanning strategy that complements chemosensing-dependent migration.

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“…Raw data quantification used to generate figures are available on FigShare at https://doi.org/10.6084/m9.figshare.25236715 (ref. 67). GSE49358 microarray data were accessed at https://www.ncbi.…”

Section: Reporting Summarymentioning

confidence: 99%

Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes

Alraies,

Rivera,

Delgado

et al. 2024

Nat Immunol

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Immune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown. Here, we identify a shape-sensing mechanism that increases the expression of the chemokine receptor CCR7 and guides dendritic cell migration from peripheral tissues to lymph nodes at steady state. This mechanism relies on the lipid metabolism enzyme cPLA2, requires nuclear envelope tensioning and is finely tuned by the ARP2/3 actin nucleation complex. We also show that this shape-sensing axis reprograms dendritic cell transcription by activating an IKKβ–NF-κB-dependent pathway known to control their tolerogenic potential. These results indicate that cell shape changes experienced by immune cells can define their migratory behavior and immunoregulatory properties and reveal a contribution of the physical properties of tissues to adaptive immunity.

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A Shape Sensing Mechanism driven by Arp2/3 and cPLA₂licenses Dendritic Cells for Migration to Lymph Nodes in Homeostasis

Cited by 7 publications

References 112 publications

Microenvironmental Regulation of Macropinocytosis Facilitates Extracellular Fluid Sampling

Microenvironmental Regulation of Macropinocytosis Facilitates Extracellular Fluid Sampling

Exocrine gland–resident memory CD8 ⁺ T cells use mechanosensing for tissue surveillance

Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes

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A Shape Sensing Mechanism driven by Arp2/3 and cPLA2licenses Dendritic Cells for Migration to Lymph Nodes in Homeostasis

Cited by 7 publications

References 112 publications

Microenvironmental Regulation of Macropinocytosis Facilitates Extracellular Fluid Sampling

Microenvironmental Regulation of Macropinocytosis Facilitates Extracellular Fluid Sampling

Exocrine gland–resident memory CD8 + T cells use mechanosensing for tissue surveillance

Cell shape sensing licenses dendritic cells for homeostatic migration to lymph nodes

Contact Info

Product

Resources

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A Shape Sensing Mechanism driven by Arp2/3 and cPLA₂licenses Dendritic Cells for Migration to Lymph Nodes in Homeostasis

Exocrine gland–resident memory CD8 ⁺ T cells use mechanosensing for tissue surveillance