Transcriptional Atlas of Intestinal Immune Cells Reveals that Neuropeptide α-CGRP Modulates Group 2 Innate Lymphoid Cell Responses

Xu, Heping; Ding, Jiarui; Porter, Caroline; Wallrapp, Antonia; Tabaka, Marcin; Ma, Sai; Fu, Shujie; Guo, Xiamei; Riesenfeld, Samantha J.; Su, Chien-Wen; Dionne, Danielle; Nguyễn, Lan; Lefkovith, Ariel; Ashenberg, Orr; Burkett, Patrick R.; Shi, Hai Ning; Rozenblatt-Rosen, Orit; Graham, Daniel B.; Kuchroo, Vijay K.; Regev, Aviv; Xavier, Ramnik J.

doi:10.1016/j.immuni.2019.09.004

Cited by 182 publications

(173 citation statements)

References 83 publications

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“…The method described previously by (Xu et al, 2019) was followed to test for cell type composition changes between healthy and infected donors. Briefly, a negative binomial regression model was used to assess if the cell type composition between healthy donors and infected cells are significantly different.…”

Section: Identifying Viral Infected Cellsmentioning

confidence: 99%

Single-cell analysis of upper airway cells reveals host-viral dynamics in influenza infected adults

Cao

Vangala

et al. 2020

Preprint

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Influenza virus infections are major causes of morbidity and mortality. Research using cultured cells, bulk tissue, and animal models cannot fully capture human disease dynamics. Many aspects of virus-host interactions in a natural setting remain unclear, including the specific cell types that are infected and how they and neighboring bystander cells contribute to the overall antiviral response. To address these questions, we 35 performed single-cell RNA sequencing (scRNA-Seq) on cells from freshly collected nasal washes from healthy human donors and donors diagnosed with acute influenza during the 2017-18 season. We describe a previously uncharacterized goblet cell population, specific to infected individuals, with high expression of MHC class II genes. Furthermore, leveraging scRNA-Seq reads, we obtained deep viral genome coverage and developed a model to rigorously identify infected cells that detected influenza infection in all epithelial cell types 40 and even some immune cells. Our data revealed that each donor was infected by a unique influenza variant and that each variant was separated by at least one unique non-synonymous difference. Our results demonstrate the power of massively-parallel scRNA-Seq to study viral variation, as well as host and viral transcriptional activity during human infection.45 50

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Section: Identifying Viral Infected Cellsmentioning

confidence: 99%

Single-cell analysis of upper airway cells reveals host-viral dynamics in influenza infected adults

Cao

Vangala

et al. 2020

Preprint

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“…CALCRL/Ramp1 engagement by CGRP binding triggers a signaling cascade in ILC2s, which signals via Gαs proteins and regulate intracellular cAMP levels. ILC2 activation is suppressed by CGRP and genetic deletion of components of the CGRP-CALCRL pathway resulted in elevated ILC2s responsiveness and type 2 inflammation in the context of helminth infection, lung inflammation and food allergy (40)(41)(42)(43). Other findings uncovered the regulation of ILC2s by neuroendocrine cells (94) and tuft cells that share many commonalities with neurons (Chat-expression, sensing, signal transmission).…”

Section: Innate Lymphoid Cells (Ilcs)mentioning

confidence: 99%

“…Additional neurotransmitters include, gamma-Aminobutyric acid (GABA), epinephrine and dopamine, but also vasoactive intestinal peptide (VIP), neuromedin U (NMU), calcitonin gene-related peptide (CGRP), Substance P, Galanin, Tachykinin, and others (32,35). With regard to neuronal regulation of immune responses, the biochemical signature of the neuron (neurotransmitters, neuropeptides) appear to be functionally most relevant, since many of the neuropeptides such as VIP, NMU, CGRP regulate immune responses via different subsets of immune cells (36)(37)(38)(39)(40)(41)(42)(43)(44). The in-depth characterization of enteric neurons may allow to identify neuronal subsets based on the expression of neurotransmitters/neuropeptides and to assign specific inflammatory functions analog to immune cells.…”

Section: Extrinsic Innervationmentioning

confidence: 99%

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Neuro-Immune Circuits Regulate Immune Responses in Tissues and Organ Homeostasis

2020

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The dense innervation of the gastro-intestinal tract with neuronal networks, which are in close proximity to immune cells, implies a pivotal role of neurons in modulating immune functions. Neurons have the ability to directly sense danger signals, adapt immune effector functions and integrate these signals to maintain tissue integrity and host defense strategies. The expression pattern of a large set of immune cells in the intestine characterized by receptors for neurotransmitters and neuropeptides suggest a tight neuronal hierarchical control of immune functions in order to systemically control immune reactions. Compelling evidence implies that targeting neuro-immune interactions is a promising strategy to dampen immune responses in autoimmune diseases such as inflammatory bowel diseases or rheumatoid arthritis. In fact, electric stimulation of vagal fibers has been shown to be an extremely effective treatment strategy against overwhelming immune reactions, even after exhausted conventional treatment strategies. Such findings argue that the nervous system is underestimated coordinator of immune reactions and underline the importance of neuro-immune crosstalk for body homeostasis. Herein, we review neuro-immune interactions with a special focus on disease pathogenesis throughout the gastro-intestinal tract.

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“…SARS-CoV-2 infection stimulates the production of prostaglandin D 2 which, in turn, upregulates the ILC2 response, leading to sequestration of lymphocytes into the lung and peripheral lymphopenia 34 . CGRP is an inhibitor of ILC216 , so we can infer that the lower levels of the peptide observed in COVID-19 patients would participate in worsening immune dysfunction and lymphopenia.Our immunofluorescence study showed immunoreactivity for RAMP1 in the walls of the major blood vessels, bronchi, and bronchioli, as well as in the epithelium of conducting airways. To the best of our knowledge this is the first morphological description of RAMP1 immunoreactivity in the human lung, but it coincides very closely with the location of CGRP binding sites as studied by radioactive ligand binding .…”

mentioning

confidence: 99%

Circulating levels of calcitonin gene-related peptide (CGRP) are lower in COVID-19 patients

Ochoa-Callejero

Garcı́a-Sanmartı́n

Villoslada-Blanco

et al. 2020

Preprint

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Background: To better understand the biology of COVID-19, we have explored the behavior of calcitonin gene-related peptide (CGRP), an angiogenic, vasodilating, and immune modulating peptide, in SARS-CoV-2 positive patients. Methods: Levels of CGRP in the serum of 57 COVID-19 patients (24 asymptomatic, 23 hospitalized in the general ward, and 10 admitted to the intensive care unit) and healthy donors (n=24) were measured by ELISA. In addition, to better understand the physiological consequences of the observed variations, we investigated by immunofluorescence the distribution of RAMP1, one of the components of the CGRP receptor, in autopsy lung specimens. Results: CGRP levels greatly decreased in COVID-19 patients (p<0.001) when compared to controls, and there were no significant differences due to disease severity, sex, age, or comorbidities. We found that COVID-19 patients treated with proton pump inhibitors had lower levels of CGRP than other patients not taking this treatment (p=0.001). RAMP1 immunoreactivity was found in smooth muscle cells of large blood vessels and the bronchial tree, and in the airways epithelium. In COVID-19 samples, RAMP1 was also found in proliferating type II pneumocytes, a common finding in these patients. Conclusions: The lower levels of CGRP should negatively impact the respiratory physiology of COVID-19 patients due to vasoconstriction, improper angiogenesis, less epithelial repair, and faulty immune response. Therefore, restoring CGRP levels in these patients may represent a novel therapeutic approach for COVID-19.

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Transcriptional Atlas of Intestinal Immune Cells Reveals that Neuropeptide α-CGRP Modulates Group 2 Innate Lymphoid Cell Responses

Abstract: Highlights d scRNA-seq reveals intestinal immune cell programs in allergic inflammation d Intestinal KLRG1 + ILC2s express a-CGRP and its receptors d a-CGRP regulates type 2 cytokine production of KLRG1 + ILC2s d a-CGRP maintains KLRG1 + ILC2 homeostasis and the type 2 immune machinery

Cited by 182 publications

References 83 publications

Single-cell analysis of upper airway cells reveals host-viral dynamics in influenza infected adults

Single-cell analysis of upper airway cells reveals host-viral dynamics in influenza infected adults

Neuro-Immune Circuits Regulate Immune Responses in Tissues and Organ Homeostasis

Circulating levels of calcitonin gene-related peptide (CGRP) are lower in COVID-19 patients

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