The histone deacetylase inhibitor valproic acid attenuates phospholipase Cγ2 and IgE-mediated mast cell activation

Rodríguez-López, Gloria M.; Soria-Castro, Rodolfo; Campillo-Navarro, Marcia; Pérez‐Tapia, Sonia Mayra; Flores-Borja, Fabián; Wong‐Baeza, Isabel; Muñoz-Cruz, Samira; López‐Santiago, Rubén; Estrada‐Parra, Sergio; Estrada-Garcı́a, Iris; Chávez‐Blanco, Alma; Chacón‐Salinas, Rommel

doi:10.1002/jlb.3ab0320-547rr

Cited by 11 publications

(17 citation statements)

References 40 publications

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“…Although over 100 genes are now associated with ASD [ 4 ], neonatal exposure to environmental risk factors such as microbial pathogens or certain drugs (e.g., the neurotoxin, valproic acid [VPA] [ 5 ]), can also provoke ASD [ 6 , 7 ]. VPA induces broad abnormalities in genes that regulate cell cycle, cell wall biogenesis, DNA repair and ion homeostasis [ 8 , 9 ]. In fact, VPA has traditionally been prescribed to control epilepsy [ 10 ], or for treatment of psychiatric conditions, such as bipolar disorders, through its modulation of GABA neurotransmission [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Phenotypic overlap between atopic dermatitis and autism

et al. 2021

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Background Autism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD). Though multifactorial in etiology, approximately 10% of ASD are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in BALB/c mice. BALB/c is an albino, laboratory-bred strain of the house mouse and is among the most widely used inbred strains used in animal experimentation. Methods We performed our studies in valproic acid (VPA)-treated BALB/c hairless mice, a standard mouse model of ASD. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5 and were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various postnatal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels. Results AD-like changes in ceramide content occurred by day one postpartum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with early appearance of cytokine markers (i.e., interleukin [IL]-4, 5, and 13), as well as mast cells in skin and brain. The high levels of interferon (IFN)γ not only in skin, but also in brain likely account for a significant decline in esterified very-long-chain N-acyl fatty acids in brain ceramides, again mimicking known IFNγ-induced changes in AD. Conclusion Baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, suggesting that the atopic diathesis could be extended to include ASD.

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Section: Introductionmentioning

confidence: 99%

Phenotypic overlap between atopic dermatitis and autism

et al. 2021

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“…The degranulation assay was carried out as described previously ( 31 ). Briefly, 2x10 5 BMMC/0.25 mL of complete medium were incubated with L.m at different MOI for 90 minutes.…”

Section: Methodsmentioning

confidence: 99%

“…The degranulation assay was carried out as described previously (31). Briefly, 2x10 5 Finally, the cells were washed and resuspended in 0.15 mL of Stain Buffer and analyzed by flow cytometry.…”

Section: Degranulation Assaymentioning

confidence: 99%

TLR2 Regulates Mast Cell IL-6 and IL-13 Production During Listeria monocytogenes Infection

et al. 2021

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Listeria monocytogenes (L.m) is efficiently controlled by several cells of the innate immunity, including the Mast Cell (MC). MC is activated by L.m inducing its degranulation, cytokine production and microbicidal mechanisms. TLR2 is required for the optimal control of L.m infection by different cells of the immune system. However, little is known about the MC receptors involved in recognizing this bacterium and whether these interactions mediate MC activation. In this study, we analyzed whether TLR2 is involved in mediating different MC activation responses during L.m infection. We found that despite MC were infected with L.m, they were able to clear the bacterial load. In addition, MC degranulated and produced ROS, TNF-α, IL-1β, IL-6, IL-13 and MCP-1 in response to bacterial infection. Interestingly, L.m induced the activation of signaling proteins: ERK, p38 and NF-κB. When TLR2 was blocked, L.m endocytosis, bactericidal activity, ROS production and mast cell degranulation were not affected. Interestingly, only IL-6 and IL-13 production were affected when TLR2 was inhibited in response to L.m infection. Furthermore, p38 activation depended on TLR2, but not ERK or NF-κB activation. These results indicate that TLR2 mediates only some MC activation pathways during L.m infection, mainly those related to IL-6 and IL-13 production.

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“…Recent structure-function studies suggested a unique ligand-transduction mechanism in MRGPRX family receptors, as they lack many of the canonical motifs associated with signaling and ligand recognition in family A G protein-coupled receptors (GPCRs) (28,29). Interestingly, allergic FcεRI-and pseudo-allergic pathways share the same signaling components further downstream, including extracellular signal-regulated kinase1/2 (ERK1/2), P38 and AKT, though kinetics differ between routes (26,(30)(31)(32). Both pathways also activate the guanosine triphosphatase (GTPase) Cdc42 upstream of actin cytoskeleton rearrangements, processes that involve the unconventional type I myosin 1f (MYO1F) (33).…”

Section: Introductionmentioning

confidence: 99%

β-arrestin-1 and β-arrestin-2 Restrain MRGPRX2-Triggered Degranulation and ERK1/2 Activation in Human Skin Mast Cells

Wang

Bal

et al. 2022

Front. Allergy

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As a novel receptor that efficiently elicits degranulation upon binding to one of its numerous ligands, MRGPRX2 has moved to the center of attention in mast cell (MC) research. Indeed, MRGPRX2 is believed to be a major component of pseudo-allergic reactions to drugs and of neuropeptide-elicited MC activation in skin diseases alike. MRGPRX2 signals via G proteins which organize downstream events ultimately leading to granule discharge. Skin MCs require both PI3K and ERK1/2 cascades for efficient exocytosis. β-arrestins act as opponents of G proteins and lead to signal termination with or without subsequent internalization. We recently demonstrated that ligand-induced internalization of MRGPRX2 requires the action of β-arrestin-1, but not of β-arrestin-2. Here, by using RNA interference, we find that both isoforms counter skin MC degranulation elicited by three MRGPRX2 agonists but not by FcεRI-aggregation. Analyzing whether this occurs through MRGPRX2 stabilization under β-arrestin attenuation, we find that reduction of β-arrestin-1 indeed leads to increased MRGPRX2 abundance, while this is not observed for β-arrestin-2. This led us speculate that β-arrestin-2 is involved in signal termination without cellular uptake of MRGPRX2. This was indeed found to be the case, whereby interference with β-arrestin-2 has an even stronger positive effect on ERK1/2 phosphorylation compared to β-arrestin-1 perturbation. Neither β-arrestin-1 nor β-arrestin-2 had an impact on AKT phosphorylation nor affected signaling via the canonical FcεRI-dependent route. We conclude that in skin MCs, β-arrestin-2 is chiefly involved in signal termination, whereas β-arrestin-1 exerts its effects by controlling MRGPRX2 abundance.

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The histone deacetylase inhibitor valproic acid attenuates phospholipase Cγ2 and IgE-mediated mast cell activation

Cited by 11 publications

References 40 publications

Phenotypic overlap between atopic dermatitis and autism

Phenotypic overlap between atopic dermatitis and autism

TLR2 Regulates Mast Cell IL-6 and IL-13 Production During Listeria monocytogenes Infection

β-arrestin-1 and β-arrestin-2 Restrain MRGPRX2-Triggered Degranulation and ERK1/2 Activation in Human Skin Mast Cells

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