Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis

Zhang, Shiqun; Edwards, Tara N.; Chaudhri, Virendra K.; Wu, Ja-Ling; Cohen, Jonathan; Hirai, Toshiro; Rittenhouse, Natalie; Schmitz, Elizabeth; Zhou, Paul Yifan; McNeil, Benjamin D.; Yang, Yi; Koerber, H. Richard; Sumpter, Tina L.; Poholek, Amanda C.; Davis, Brian M.; Albers, Kathryn M.; Singh, Harinder; Kaplan, Daniel H.

doi:10.1016/j.cell.2021.03.002

Cited by 104 publications

(78 citation statements)

References 77 publications

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“…On the basis of recent research, the roles of MCs in the sensitization and elicitation phases of CHS have been considered as follows: First, during the sensitization phase (which is equivalent to the condition of ICD), MCs are activated directly or indirectly by haptens to release a diverse spectrum of mediators, including histamine and TNF-α, which induce vasodilatation and neutrophil recruitment [ 53 , 55 ]. Consistently, ICD-induced ear swelling, which depends on Mrgprb2 activation [ 49 ], is substantially reduced in MC-specific Pla2g3 -deficient mice. Interactions between MCs and dendritic cells (DCs) by direct contact or MC-secreted TNF-α can amplify DC migration into the draining lymph nodes, where DCs prime naïve T cells to become effector T cells via Ag presentation [ 67 ].…”

Section: Discussionmentioning

confidence: 84%

“…It has recently been shown that ICD requires CTMC activation in a manner dependent on substance P released from nociceptive neurons and MrgprB2 expressed on MCs [ 49 ]. MrgprB2 functions as an activating receptor for IgE-independent CTMC degranulation in response to multiple exogenous and endogenous ligands such as C48/80 and substance P [ 48 , 49 , 50 , 51 ]. We observed that the IgE-independent, C48/80-induced anaphylactic response was markedly lower in Pla2g3 fl/fl Mcpt5 - Cre mice than in Pla2g3 fl/fl mice ( Figure 3 F).…”

Section: Resultsmentioning

confidence: 99%

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Mast Cell-Specific Deletion of Group III Secreted Phospholipase A2 Impairs Mast Cell Maturation and Functions

Taketomi

Endo

Higashi

et al. 2021

Cells

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Tissue-resident mast cells (MCs) have important roles in IgE-associated and -independent allergic reactions. Although microenvironmental alterations in MC phenotypes affect the susceptibility to allergy, understanding of the regulation of MC maturation is still incomplete. We previously reported that group III secreted phospholipase A2 (sPLA2-III) released from immature MCs is functionally coupled with lipocalin-type prostaglandin D2 (PGD2) synthase in neighboring fibroblasts to supply a microenvironmental pool of PGD2, which in turn acts on the PGD2 receptor DP1 on MCs to promote their proper maturation. In the present study, we reevaluated the role of sPLA2-III in MCs using a newly generated MC-specific Pla2g3-deficient mouse strain. Mice lacking sPLA2-III specifically in MCs, like those lacking the enzyme in all tissues, had immature MCs and displayed reduced local and systemic anaphylactic responses. Furthermore, MC-specific Pla2g3-deficient mice, as well as MC-deficient KitW-sh mice reconstituted with MCs prepared from global Pla2g3-null mice, displayed a significant reduction in irritant contact dermatitis (ICD) and an aggravation of contact hypersensitivity (CHS). The increased CHS response by Pla2g3 deficiency depended at least partly on the reduced expression of hematopoietic PGD2 synthase and thereby reduced production of PGD2 due to immaturity of MCs. Overall, our present study has confirmed that MC-secreted sPLA2-III promotes MC maturation, thereby facilitating acute anaphylactic and ICD reactions and limiting delayed CHS response.

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Mast Cell-Specific Deletion of Group III Secreted Phospholipase A2 Impairs Mast Cell Maturation and Functions

Taketomi

Endo

Higashi

et al. 2021

Cells

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“…CGRP and SP are pro-inflammatory peptides that play key roles in neurogenic inflammation; CGRP is a potent vasodilator and substance P induces mast cell degranulation (Lim et al, 2017). In contrast, NP neurons have been reported to suppress mast cell reactivity (Zhang et al, 2021). Notably, several studies have demonstrated that cutaneous IB4-binding neurons transduce mechanical stimuli in the non-noxious range, and optogenetic stimulation of these neurons fails to evoke nocifensive behavior unless they are sensitized by tissue injury, calling into question whether these neurons act as nociceptors in healthy tissue (Warwick et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Members of the CUGBP Elav-Like Family of RNA-Binding Proteins are Expressed in Distinct Populations of Primary Sensory Neurons

Grlickova-Duzevik

Michael

McGrath-Conwell

et al. 2021

Preprint

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Primary sensory Dorsal Root Ganglia (DRG) neurons are diverse, with distinct populations that respond to specific stimuli. Previously, we observed that functionally distinct populations of DRG neurons express mRNA transcript variants with different 3` untranslated regions (3`UTRs). 3`UTRs harbor binding sites for interaction with RNA-binding proteins (RBPs) critical for targeting mRNAs to subcellular domains, modulating transcript stability and regulating the rate of translation. In the current study we sought to determine if 3`UTR-binding proteins are restricted to specific DRG neuron populations. Analysis of publicly available single-cell RNA-Sequencing (scRNA-Seq) data generated from adult mice revealed that 17 3`UTR-binding RBPs were enriched in specific populations of DRG neurons. This included 4 members of the CUGBP Elav-Like Family (CELF). CELF2 and CELF4 were enriched in peptidergic, CELF6 in both peptidergic and nonpeptidergic and CELF3 in tyrosine hydroxylase-expressing neurons. CELF4 is a known regulator of neural excitability, likely through modulation of protein synthesis via binding to interaction sites within the 3`UTRs of mRNAs. Immunofluorescence studies showed 60% of CELF4+ neurons are small diameter C fibers and 33% medium diameter myelinated (likely Aδ) fibers. Co-expression analyses using transcriptomic data and quantitative immunofluorescence revealed that CELF4 is enriched in nociceptive neurons that express GFRA3, CGRP and the capsaicin receptor TRPV1. Finally, genes with CELF4 binding motifs expressed in CELF4+ neurons are significantly associated with gene ontology (GO) terms such as RNA-binding and translation. We propose that CELF4 may therefore control a novel regulon that coordinates the translation of mRNAs encoding components of the protein translation apparatus in nociceptors.

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“…To our knowledge, there are no further studies that have investigated the effect of mast cell activation and non-neuronal histamine directly on the CNS in vivo. However, bi-directional communication was recently demonstrated between mast cells and neurons in the skin (Zhang et al, 2021), which may demonstrate a role in the mediation of epidermal and dermal inflammation. Mast cell sources of histamine have also been implicated in the pathophysiology of neuropathic pain (Rosa and Fantozzi, 2013).…”

Section: Mast Cell Interactions With Astrocytes and Neuronsmentioning

confidence: 99%

Histamine, Neuroinflammation and Neurodevelopment: A Review

Carthy

Ellender

2021

Front. Neurosci.

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The biogenic amine, histamine, has been shown to critically modulate inflammatory processes as well as the properties of neurons and synapses in the brain, and is also implicated in the emergence of neurodevelopmental disorders. Indeed, a reduction in the synthesis of this neuromodulator has been associated with the disorders Tourette’s syndrome and obsessive-compulsive disorder, with evidence that this may be through the disruption of the corticostriatal circuitry during development. Furthermore, neuroinflammation has been associated with alterations in brain development, e.g., impacting synaptic plasticity and synaptogenesis, and there are suggestions that histamine deficiency may leave the developing brain more vulnerable to proinflammatory insults. While most studies have focused on neuronal sources of histamine it remains unclear to what extent other (non-neuronal) sources of histamine, e.g., from mast cells and other sources, can impact brain development. The few studies that have started exploring this in vitro, and more limited in vivo, would indicate that non-neuronal released histamine and other preformed mediators can influence microglial-mediated neuroinflammation which can impact brain development. In this Review we will summarize the state of the field with regard to non-neuronal sources of histamine and its impact on both neuroinflammation and brain development in key neural circuits that underpin neurodevelopmental disorders. We will also discuss whether histamine receptor modulators have been efficacious in the treatment of neurodevelopmental disorders in both preclinical and clinical studies. This could represent an important area of future research as early modulation of histamine from neuronal as well as non-neuronal sources may provide novel therapeutic targets in these disorders.

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Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis

Cited by 104 publications

References 77 publications

Mast Cell-Specific Deletion of Group III Secreted Phospholipase A2 Impairs Mast Cell Maturation and Functions

Mast Cell-Specific Deletion of Group III Secreted Phospholipase A2 Impairs Mast Cell Maturation and Functions

Members of the CUGBP Elav-Like Family of RNA-Binding Proteins are Expressed in Distinct Populations of Primary Sensory Neurons

Histamine, Neuroinflammation and Neurodevelopment: A Review

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