A Mast-Cell-Specific Receptor Mediates Neurogenic Inflammation and Pain

Green, Dustin P.; Limjunyawong, Nathachit; Gour, Naina; Pundir, Priyanka; Dong, Xinzhong

doi:10.1016/j.neuron.2019.01.012

Cited by 296 publications

(256 citation statements)

References 32 publications

(30 reference statements)

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“…The receptors for other neuropeptides, Tac1, Adcyap1, and Gal (Tacr1, Adcyap1r1, and Galr2 & Galr1, respectively) were uniquely expressed by NES, identifying substance P, 20 PACAP, and galanin as potential signaling mediators between LN-innervating neurons and NES. Notably, the recently identified alternative substance P receptor Mrgprb2 was almost exclusively expressed at high level in LN mast cells, suggesting a substance P/Mrgprb2 mediated sensory neuron-mast cell connection analogous to what 510 was described in the skin (Green et al, 2019). By contrast, classic neuropeptides were not a primary mode of communication between LN-innervating sensory neurons and LN endothelial cells.…”

Section: S5o See Methods)mentioning

confidence: 68%

Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

Huang

Ziegler

Austin

et al. 2019

Preprint

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Immune responses within barrier tissues are regulated, in part, by nociceptors, specialized peripheral sensory neurons that detect noxious stimuli. Previous work has shown that nociceptor ablation not only alters local responses to immune challenge at peripheral sites, but also within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Indeed, although sympathetic innervation of LNs is well documented, it has been unclear whether the LN parenchyma itself is innervated by sensory neurons. Here, using a combination of high-resolution imaging, retrograde viral tracing, single-cell 30 transcriptomics (scRNA-seq), and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is preferentially located in the outermost cortex of skin-draining LNs. Transcriptomic profiling revealed that there are at least four discrete subsets of sensory neurons that innervate LNs with a predominance of peptidergic nociceptors, and an innervation pattern that is distinct from that in the surrounding skin. To uncover potential LN-resident communication partners for LN-innervating sensory neurons, we employed scRNA-seq to generate a draft atlas of all murine LN cells and, based on receptor-ligand expression patterns, nominated candidate target populations among stromal and immune cells. Using selective optogenetic stimulation of LN-innervating sensory axons, we directly experimentally tested our inferred connections. Acute neuronal activation triggered rapid transcriptional changes preferentially within our top-ranked putative interacting partners, principally endothelium and other nodal stroma cells, as well as several innate leukocyte populations. Thus, LNs are monitored by a unique 40 population of sensory neurons that possesses immunomodulatory potential. 840 and Harvard. J.O

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Section: S5o See Methods)mentioning

confidence: 68%

Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

Huang

Ziegler

Austin

et al. 2019

Preprint

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“…As well known, mast cells mediate neurogenic inflammation and pain [28]. The activated and degranulating mast cells may exert indirect effects on the development of neuropathic pain [29].…”

Section: Mifepristone Inhibits the Infiltration And Activity Of Degramentioning

confidence: 99%

The new application of mifepristone in the relief of adenomyosis-caused dysmenorrhea

Che

Wang

et al. 2020

Int. J. Med. Sci.

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Background: Adenomyosis is a quite common gynecological disorder and above 30% of patients have typical secondary and progressive dysmenorrhea. Current treatments still have many disadvantages and thereby the novel treatment aiming to relieve dysmenorrhea still needs to be further investigated. Mifepristone is a wonderful drug because it is effective, safe and cheap in many diseases including adenomyosis. In this study, we aim to investigate if mifepristone could be used in the treatment of adenomyosis-associated dysmenorrhea. Methods: Human primary endometrial epithelial and stromal cells from adenomyosis patients were isolated and treated with mifepristone. RNA-sequencing was then performed to detect the gene changes of pain-related inflammatory mediators. Meanwhile, the effect of mifepristone on the infiltration and degranulation of mast cells were investigated in adenomyosis lesions. Additionally, the role of mifepristone on the density of nerve fibers was also studied in the ectopic endometrium. At last, to evaluate the therapeutic efficacy of mifepristone on dysmenorrhea of adenomyosis, twenty participants were included and the visual analog scale (VAS) score was assessed and compared before and after treatment with mifepristone. Results: We demonstrated that mifepristone reduced the secretion of IL-6 and TNF-α from endometrial epithelial and stromal cells, restricted the infiltration and degranulation of mast cells in eutopic and ectopic endometrium and decreased the density of nerve fibers by inhibiting the migration capacity of nerve cells in adenomyosis. Meanwhile, we found that mifepristone could significantly relieve dysmenorrhea of adenomyosis. Conclusion: The findings demonstrated that mifepristone could be applied in the treatment of dysmenorrhea for the adenomyosis patients.

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“…SP also modulated the immune response to microbial infection (29). It was recently demonstrated that SP could promote the migration and activation of mast cells, inducing the release of multiple pro-inflammatory cytokines and chemokines (30). Noteworthy, SP directly caused the secretion of IL-8 in human colonic epithelial cell lines (31), hinting at the potential proinflammatory role of SP in intestine.…”

Section: Trp Channels In the Gi Tract And Related Neuropeptidesmentioning

confidence: 99%

Transient Receptor Potential Channels and Inflammatory Bowel Disease

Chen

Zhu

et al. 2020

Front. Immunol.

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The transient receptor potential (TRP) cation channels are present in abundance across the gastrointestinal (GI) tract, serving as detectors for a variety of stimuli and secondary transducers for G-protein coupled receptors. The activation of TRP channels triggers neurogenic inflammation with related neuropeptides and initiates immune reactions by extra-neuronally regulating immune cells, contributing to the GI homeostasis. However, under pathological conditions, such as inflammatory bowel disease (IBD), TRP channels are involved in intestinal inflammation. An increasing number of human and animal studies have indicated that TRP channels are correlated to the visceral hypersensitivity (VHS) and immune pathogenesis in IBD, leading to an exacerbation or amelioration of the VHS or intestinal inflammation. Thus, TRP channels are a promising target for novel therapeutic methods for IBD. In this review, we comprehensively summarize the functions of TRP channels, especially their potential roles in immunity and IBD. Additionally, we discuss the contradictory findings of prior studies and offer new insights with regard to future research.

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A Mast-Cell-Specific Receptor Mediates Neurogenic Inflammation and Pain

Cited by 296 publications

References 32 publications

Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

The new application of mifepristone in the relief of adenomyosis-caused dysmenorrhea

Transient Receptor Potential Channels and Inflammatory Bowel Disease

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