KIT as a master regulator of the mast cell lineage

Tsai, Mindy; Valent, Peter; Galli, Stephen J.

doi:10.1016/j.jaci.2022.04.012

Cited by 52 publications

(45 citation statements)

References 135 publications

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“…Thus, targeting single pathways on MCs may not be sufficient to broadly reduce MC activity 48 . To address these shortcomings, KIT targeting strategies have been developed to reduce MC numbers 49 . Indeed, administration of a single dose of the anti-KIT mAb leads to ablation of skin MCs and improvement of chronic urticarias 50 .…”

Section: Discussionmentioning

confidence: 99%

Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells

et al. 2022

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Mast cells (MC) are key drivers of allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 is an immunoregulatory receptor found on MCs. While it is recognized that engaging Siglecs with antibodies mediates inhibition across immune cells, the mechanisms that govern this agonism are not understood. Here we generated Siglec-6 mAb clones (AK01 to AK18) to better understand Siglec-6-mediated agonism. Siglec-6 mAbs displayed epitope-dependent receptor internalization and inhibitory activity. We identified a Siglec-6 mAb (AK04) that required Fc-mediated interaction for receptor internalization and induced inhibition and antibody-dependent cellular phagocytosis against MCs. AK04-mediated MC inhibition required Siglec-6 immunoreceptor tyrosine-based inhibitory motif (ITIM) and ITIM-like domains and was associated with receptor cluster formation containing inhibitory phosphatases. Treatment of humanized mice with AK04 inhibited systemic anaphylaxis with a single dose and reduced MCs with chronic dosing. Our findings suggest Siglec-6 activity is epitope dependent and highlight an agonistic Siglec-6 mAb as a potential therapeutic approach in allergic disease.

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Section: Discussionmentioning

confidence: 99%

Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells

et al. 2022

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“…MCs in the skin connective tissue of adult mice originate from definitive hematopoiesis and maintain themselves independently from the bone marrow 9 . Their differentiation and survival critically depend on KIT ligand (KITLG; also known as stem cell factor (SCF)), which signals through the receptor tyrosine kinase KIT 10 . However, it remains unknown how MCs move and strategically position to maintain their survival and cellular network distribution in physiological tissues.…”

mentioning

confidence: 99%

Slow integrin-dependent migration organizes networks of tissue-resident mast cells

et al. 2023

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Immune cell locomotion is associated with amoeboid migration, a flexible mode of movement, which depends on rapid cycles of actin polymerization and actomyosin contraction1. Many immune cells do not necessarily require integrins, the major family of adhesion receptors in mammals, to move productively through three-dimensional tissue spaces2,3. Instead, they can use alternative strategies to transmit their actin-driven forces to the substrate, explaining their migratory adaptation to changing external environments4–6. However, whether these generalized concepts apply to all immune cells is unclear. Here, we show that the movement of mast cells (immune cells with important roles during allergy and anaphylaxis) differs fundamentally from the widely applied paradigm of interstitial immune cell migration. We identify a crucial role for integrin-dependent adhesion in controlling mast cell movement and localization to anatomical niches rich in KIT ligand, the major mast cell growth and survival factor. Our findings show that substrate-dependent haptokinesis is an important mechanism for the tissue organization of resident immune cells.

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“…Moreover, CD117 can be instrumental in the diagnosis of some tumors, such as gastrointestinal ones where MCs are abundant (8). Experiments in mice have shown that ckit is encoded at the mouse locus where it affects immature germ cells (9).…”

Section: Introductionmentioning

confidence: 99%

Activation of Mast Cells by Neuropeptides: The Role of Pro-inflammatory and Anti-Inflammatory Cytokines

Lauritano¹,

Mastrangelo²,

D’Ovidio³

et al. 2023

Preprint

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Mass cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in scientific literature and is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptides and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.

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KIT as a master regulator of the mast cell lineage

Cited by 52 publications

References 135 publications

Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells

Discovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells

Slow integrin-dependent migration organizes networks of tissue-resident mast cells

Activation of Mast Cells by Neuropeptides: The Role of Pro-inflammatory and Anti-Inflammatory Cytokines

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