Kindlin-3–mediated integrin adhesion is dispensable for quiescent but essential for activated hematopoietic stem cells

Ruppert, Raphael; Moser, Markus; Sperandio, Markus; Rognoni, Emanuel; Orban, Martin; Liu, Wen-Hsin; Schulz, Ansgar; Oostendorp, Robert A.J.; Maßberg, Steffen; Fässler, Reinhard

doi:10.1083/jcb.2105oia171

Cited by 11 publications

(22 citation statements)

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“…Recently, the role of Kindlin‐3 in hematopoiesis was uncovered. Using Kindlin‐3‐deficient mice, they showed that Kindlin‐3–deficient HSC were quiescence and remained in the BM but became hyperactivated and lost in the circulation when they were transplanted into irradiated recipients . These observations together with our findings expand our understanding of integrin β2 from cell adhesion to regulation of hematopoiesis and myelopoiesis.…”

Section: Discussionsupporting

confidence: 70%

The Impact of Integrin β2 on Granulocyte/Macrophage Progenitor Proliferation

et al. 2019

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Previously, we reported that although the HSPC frequency in bone marrow cells (BMC) was comparable between β2−/− and β2+/+ mice, transplantation of β2−/− BMC into lethally irradiated CD45.1 recipient resulted in more myeloid cell production than β2+/+ BMC. The objective of this study is to address if integrin β2 deficiency skews granulocyte/macrophage progenitor (GMP) proliferation. FACS analysis demonstrated that GMP frequency and cell number were higher and megakaryocyte/erythrocyte progenitor frequency and cell number were lower in β2−/− mice than β2+/+ mice. However, the common myeloid progenitors (CMP) frequency and cell number were similar between the two groups. The increased GMP number was due to GMP proliferation as evidenced by the percentage of BrdU‐incorporating GMP. Whole genome transcriptome analysis identified increased FcεRIα expression in β2−/− CMP compared to β2+/+ CMP. FcεRIα expression on β2−/− GMP was detected increased in β2−/− mice by qRT‐PCR and FACS. Although transplantation of FcεRIαhi GMP or FcεRIαlo GMP into lethally irradiated CD45.1 recipient resulted in comparable myeloid cell production, transplantation of β2 deficient FcεRIαhi GMP generated more myeloid cells than β2+/+ FcεRIαhi GMP. GATA2 expression was increased in β2−/− GMP. Using a luciferase reporter assay, we demonstrated that mutation of the GATA2 binding site in the FcεRIα promoter region diminished FcεRIα transcription. In vitro, the addition of IgE, the ligand of FcεRIα, promoted GMP expansion, which was abrogated by inhibition of JNK phosphorylation. Integrin β2 deficiency promoted GMP proliferation and myeloid cell production, which was mediated via FcεRIα/IgE‐induced JNK phosphorylation in GMP. Stem Cells 2019;37:430–440

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Section: Discussionsupporting

confidence: 70%

The Impact of Integrin β2 on Granulocyte/Macrophage Progenitor Proliferation

et al. 2019

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“…1,8 To enable the disruption of the kindlin-3 gene at later stages or in specific hematopoietic cells, we generated a conditional kindlin-3 mouse by flanking exon 3-6 with loxP sites (supplemental Figure 1A-C). 21 An intercross of these kindlin-3 floxed (K3fl/fl) mice with a deleter Cre strain produced offspring BLOOD, 10 DECEMBER 2015 x VOLUME 126, NUMBER 24 BLOOD…”

Section: Generation Of Conditional and Hypomorphic Kindlin-3 Mouse Mumentioning

confidence: 99%

Minimal amounts of kindlin-3 suffice for basal platelet and leukocyte functions in mice

Klapproth

Moretti

Zeiler

et al. 2015

Blood

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Key Points• As little as 5% of kindlin-3 is sufficient to maintain basal platelet and leukocyte functions.• Platelets and neutrophils contain stoichiometric quantities of kindlin-3 and talin-1.Hematopoietic cells depend on integrin-mediated adhesion and signaling, which is induced by kindlin-3 and talin-1. To determine whether platelet and polymorphonuclear neutrophil (PMN) functions require specific thresholds of kindlin-3, we generated mouse strains expressing 50%, 10%, or 5% of normal kindlin-3 levels. We report that in contrast to kindlin-3-null mice, which die perinatally of severe bleeding and leukocyte adhesion deficiency, mice expressing as little as 5% of kindlin-3 were viable and protected from spontaneous bleeding and infections. However, platelet adhesion and aggregation were reduced in vitro and bleeding times extended. Similarly, leukocyte adhesion, extravasation, and bacterial clearance were diminished. Quantification of protein copy numbers revealed stoichiometric quantities of kindlin-3 and talin-1 in platelets and neutrophils, indicating that reduction of kindlin-3 in our mouse strains progressively impairs the cooperation with talin-1. Our findings show that very low levels of kindlin-3 enable basal platelet and neutrophil functions, whereas in stress situations such as injury and infection, platelets and neutrophils require a maximum of functional integrins that is achieved with high and stoichiometric quantities of kindlin-3 and talin-1. (Blood. 2015;126(24):2592-2600

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“…What remains unknown is how force acting on LFA‐1 bond clusters results in tight engagement between LFA‐1 and Kindlin‐3 and how it engages locally with CRAC channels in modulation of local Ca 2+ release. It has been reported that as little as 5% of physiologic Kindlin‐3 levels in haematopoietic cells are essential for the retention in bone marrow and sufficient for embryonic and postnatal development, but exposure to stress such as infection at this low level of Kindlin‐3 significantly impaired the capacity for PMN adhesion and host response . Thus, a ratio of two LFA‐1 to each Kindlin‐3 appears to be the optimal configuration for homeostatic regulation of adhesive function and to prevent spontaneous bleeding and microbial infections.…”

Section: Role Of Adaptor Molecules In Local Regulation Of Ca2+ Fluxmentioning

confidence: 99%

“…It has been reported that as little as 5% of physiologic Kindlin-3 levels in haematopoietic cells are essential for the retention in bone marrow and sufficient for embryonic and postnatal development, but exposure to stress such as infection at this low level of Kindlin-3 significantly impaired the capacity for PMN adhesion and host response. 47,53 Thus, a ratio of two LFA-1 to each Kindlin-3 appears to be the optimal configuration for homeostatic regulation of adhesive function and to prevent spontaneous bleeding and microbial infections. We propose that the local engagement of adhesion receptors and regulation of cytosolic Ca 2+ are rate-limiting steps in mediating where and when neutrophils are activated to arrest and initiate a migratory phenotype, events that serve as a gatekeeper in neutrophil recruitment to sites of inflammation.…”

Section: Molecules In Local Regulation Of Ca 2 + Fluxmentioning

confidence: 99%

Calcium signalling and related ion channels in neutrophil recruitment and function

Immler

Simon

Sperandio

2018

Eur J Clin Investigation

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116

108

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The recruitment of neutrophils to sites of inflammation, their battle against invading microorganisms through phagocytosis and the release of antimicrobial agents is a highly coordinated and tightly regulated process that involves the interplay of many different receptors, ion channels and signalling pathways. Changes in intracellular calcium levels, caused by cytosolic Ca store depletion and the influx of extracellular Ca via ion channels, play a critical role in synchronizing neutrophil activation and function. In this review, we provide an overview of how Ca signalling is initiated in neutrophils and how changes in intracellular Ca levels modulate neutrophil function.

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Kindlin-3–mediated integrin adhesion is dispensable for quiescent but essential for activated hematopoietic stem cells

Cited by 11 publications

References 1 publication

The Impact of Integrin β2 on Granulocyte/Macrophage Progenitor Proliferation

The Impact of Integrin β2 on Granulocyte/Macrophage Progenitor Proliferation

Minimal amounts of kindlin-3 suffice for basal platelet and leukocyte functions in mice

Calcium signalling and related ion channels in neutrophil recruitment and function

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