Mice Lacking the Inhibitory Collagen Receptor LAIR-1 Exhibit a Mild Thrombocytosis and Hyperactive Platelets

Smith, Christopher W.; Thomas, Steven G.; Raslan, Zaher; Patel, Pushpa; Byrne, Maxwell; Lordkipanidzé, Marie; Bem, Danai; Meyaard, Linde; Senis, Yotis A.; Watson, Steve P.; Mazharian, Alexandra

doi:10.1161/atvbaha.117.309253

Cited by 28 publications

(37 citation statements)

References 29 publications

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“…tyrosine-based inhibition motif signaling components such as the leukocyte-associated immunoglobulin-like receptor-1 or the associated signaling molecules, Src-like adapter proteins SLAP and SLAP2, in which platelets showed a (hem) immunoreceptor tyrosine-based activation motif (ITAM)-specific hyperreactivity. 50,51 Moreover, hyperreactive Stim1 1/Sax platelets (due to a constitutive store-operated Ca 21 entry) showed selectively impaired (hem)ITAM signaling. 52 Finally, Ras GTPase-activating protein 3 mutant mice showed increased platelet activation and a markedly accelerated platelet turnover that was independent of splenic clearance.…”

Section: Discussionmentioning

confidence: 99%

Twinfilin 2a regulates platelet reactivity and turnover in mice

Stritt

Beck

Becker

et al. 2017

Blood

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Regulated reorganization of the actin cytoskeleton is a prerequisite for proper platelet production and function. Consequently, defects in proteins controlling actin dynamics have been associated with platelet disorders in humans and mice. Twinfilin 2a (Twf2a) is a small actin-binding protein that inhibits actin filament assembly by sequestering actin monomers and capping filament barbed ends. Moreover, Twf2a binds heterodimeric capping proteins, but the role of this interaction in cytoskeletal dynamics has remained elusive. Even though Twf2a has pronounced effects on actin dynamics in vitro, only little is known about its function in vivo. Here, we report that constitutive Twf2a-deficient mice () display mild macrothrombocytopenia due to a markedly accelerated platelet clearance in the spleen. platelets showed enhanced integrin activation and α-granule release in response to stimulation of (hem) immunoreceptor tyrosine-based activation motif (ITAM) and G-protein-coupled receptors, increased adhesion and aggregate formation on collagen I under flow, and accelerated clot retraction and spreading on fibrinogen. In vivo, Twf2a deficiency resulted in shortened tail bleeding times and faster occlusive arterial thrombus formation. The hyperreactivity of platelets was attributed to enhanced actin dynamics, characterized by an increased activity of n-cofilin and profilin 1, leading to a thickened cortical cytoskeleton and hence sustained integrin activation by limiting calpain-mediated integrin inactivation. In summary, our results reveal the first in vivo functions of mammalian Twf2a and demonstrate that Twf2a-controlled actin rearrangements dampen platelet activation responses in a n-cofilin- and profilin 1-dependent manner, thereby indirectly regulating platelet reactivity and half-life in mice.

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Section: Discussionmentioning

confidence: 99%

Twinfilin 2a regulates platelet reactivity and turnover in mice

Stritt

Beck

Becker

et al. 2017

Blood

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“…Laser-induced injury of arterioles in the cremaster muscle and ferric chloride (FeCl 3 )-induced injury of carotid arteries were performed and analyzed as previously described. 42…”

Section: In Vivo Thrombosis Assaysmentioning

confidence: 99%

Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148

Mori

Nagy

Nunzio

et al. 2018

Blood

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Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, but it remains unclear how they are regulated. Here, we show that ablation of C-terminal Src kinase (Csk) and receptor-like protein tyrosine-phosphatase CD148 in mice results in a dramatic increase in platelet SFK activity, demonstrating that these proteins are essential regulators of platelet reactivity. Paradoxically, Csk/CD148-deficient mice exhibit reduced in vivo and ex vivo thrombus formation and increased bleeding following injury rather than a prothrombotic phenotype. This is a consequence of multiple negative feedback mechanisms, including downregulation of the immunoreceptor tyrosine-based activation motif (ITAM)- and hemi-ITAM-containing receptors glycoprotein VI (GPVI)-Fc receptor (FcR) γ-chain and CLEC-2, respectively and upregulation of the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B and its interaction with the tyrosine phosphatases Shp1 and Shp2. Results from an analog-sensitive Csk mouse model demonstrate the unconventional role of SFKs in activating ITIM signaling. This study establishes Csk and CD148 as critical molecular switches controlling the thrombotic and hemostatic capacity of platelets and reveals cell-intrinsic mechanisms that prevent pathological thrombosis from occurring.

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“…LAIR-1 is a better characterized collagen receptor which belongs to the ITIM receptor family. Platelets of mice lacking LAIR-1 are still hyperreactive upon collagen stimulation, although the receptor is absent on platelets [4]. When we co-stained LAIR-1 together with MKs (GPIX) within bone marrow of wt and dko mice, we could detect single GPIX-negative cells that were strongly positive for LAIR-1, likely being early megakaryocytic progenitor cells.…”

Section: Other Collagen Receptors (Compensatory Mechanisms)mentioning

confidence: 90%

Impact ofItga2-Gp6-double collagen receptor deficient mice for bone marrow megakaryocytes and platelets

Semeniak

Faber

Öftering

et al. 2019

Preprint

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The two main collagen receptors on platelets, GPVI and integrin α2β1, play an important role for the recognition of exposed collagen at sites of vessel injury, which leads to platelet activation and subsequently stable thrombus formation. Both receptors are already expressed on megakaryocytes, the platelet forming cells within the bone marrow. Megakaryocytes are in permanent contact with collagen filaments in the marrow cavity and at the basal lamina of sinusoids without obvious preactivation. The role of both collagen receptors for megakaryocyte maturation and thrombopoiesis is still poorly understood. To investigate the function of both collagen receptors, we generated mice that are double deficient for Gp6 and Itga2. Flow cytometric analyses revealed that the deficiency of both receptors had no impact on platelet number and the expected lack in GPVI responsiveness. Integrin activation

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Mice Lacking the Inhibitory Collagen Receptor LAIR-1 Exhibit a Mild Thrombocytosis and Hyperactive Platelets

Cited by 28 publications

References 29 publications

Twinfilin 2a regulates platelet reactivity and turnover in mice

Twinfilin 2a regulates platelet reactivity and turnover in mice

Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148

Impact ofItga2-Gp6-double collagen receptor deficient mice for bone marrow megakaryocytes and platelets

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