Optogenetic activation of local colonic sympathetic innervations attenuates colitis by limiting immune cell extravasation

Schiller, Maya; Azulay-Debby, Hilla; Boshnak, Nadia; Elyahu, Yehezqel; Korin, Ben; Ben-Shaanan, Tamar L.; Koren, Tamar; Krot, Maria; Rolls, Asya

doi:10.1016/j.immuni.2021.04.007

Cited by 34 publications

(26 citation statements)

References 93 publications

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“…The colonic proximal and distal segments have different mucosal morphologies, and density and characteristics of enteric neurons linked to different functions including the facilitation of the absorption of excess fluid and electrolytes, mixing, storage of liquid feces, and fermentation of food residues, taking place in the proximal segment. There are distinct motor pattern of activity and motor function in the proximal and distal colon (Zygulska et al, 2018 ; Mogilevski et al, 2019 ; Schiller et al, 2021 ; Nestor-Kalinoski et al, 2022 ). The complex function of the proximal colon is apparent by higher neuronal density and more intricate circuitry in the myenteric plexus vs. the distal colon (Smith and Koh, 2017 ; Li et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…We also used PHP.S-tdTf, an engineered AAV9 variant vector with farnesylated fluorophore as a new tool to profile the distribution of transduced nerve fibers. The focus on the colon was to gain insights into the profile of neurons responsive to systemic AAV vectors for potential development of neuromodulation and drug therapies to treat colonic diseases, such as inflammatory bowel and colon cancer (Zygulska et al, 2018 ; Mogilevski et al, 2019 ; Schiller et al, 2021 ). Based on the segmental difference in the transduction of the colon, we assessed whether such a feature was specific to the colon or also found in other parts of the GI tract from the esophagus to ileum.…”

Section: Introductionmentioning

confidence: 99%

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Transduction of Systemically Administered Adeno-Associated Virus in the Colonic Enteric Nervous System and c-Kit Cells of Adult Mice

et al. 2022

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Systemic delivery of adeno-associated virus (AAV) vectors transduces the enteric nervous system. However, less is known on the mapping and morphological and neurochemical characterization in the adult mouse colon. We used AAV9-CAG-GFP (AAV9) and AAV-PHP.S-hSyn1-tdTomato farnesylated (PHP.S-tdTf) to investigate the segmental distribution, morphologies and neurochemical coding of the transduction. The vectors were retro-orbitally injected in male and female adult mice, and 3 weeks later, the colon was prepared for microcopy with or without immunohistochemistry for neuronal and non-neuronal markers. In contrast to the distributions in neonatal and juvenile rodents, the AAV transduction in neurons and/or nerve fibers was the highest in the proximal colon, decreased gradually in the transverse, and was sparse in the distal colon without difference between sexes. In the proximal colon, the AAV9-transduced myenteric neurons were unevenly distributed. The majority of enteric neurons did not have AAV9 expression in their processes, except those with big soma with or without variously shaped dendrites, and a long axon. Immunolabeling demonstrated that about 31% neurons were transduced by AAV9, and the transduction was in 50, 28, and 31% of cholinergic, nitrergic, and calbindin-positive myenteric neurons, respectively. The nerve fiber markers, calcitonin gene-related peptide alpha, tyrosine hydroxylase or vasoactive intestinal polypeptide co-localized with AAV9 or PHP.S-tdTf in the mucosa, and rarely in the myenteric plexus. Unexpectedly, AAV9 expression appeared also in a few c-Kit immunoreactive cells among the heavily populated interstitial cells of Cajal (ICC). In the distal colon, the AAV transduction appeared in a few nerve fibers mostly the interganglionic strands. Other types of AAV9 and AAV-PHP vectors induced a similar colonic segmental difference which is not colon specific since neurons were transduced in the small intestine and gastric antrum, while little in the gastric corpus and none in the lower esophagus.ConclusionThese findings demonstrate that in adult mice colon that there is a rostro-caudal decrease in the transduction of systemic delivery of AAV9 and its variants independent of sex. The characterization of AAV transduction in the proximal colon in cholinergic and nitrergic myenteric neurons along with a few ICC suggests implications in circuitries regulating motility.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transduction of Systemically Administered Adeno-Associated Virus in the Colonic Enteric Nervous System and c-Kit Cells of Adult Mice

et al. 2022

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“…Despite these limitations, mouse models can certainly add to our understanding of neuro-immune interactions. For example, recent mouse studies showed clear anti-inflammatory effects of SNS activation on immune-cell traffic and function [e.g., 107 ]. However, selection of suitable mouse strains, adequate housing conditions (e.g., thermoneutrality, enriched environment, adequate group size), stress-minimizing blood sampling and killing procedures, short-term and thus more physiological manipulations of stress systems, and additional readouts including sleep, other behaviors (nesting, burrowing, locomotion, food intake), and blood parameters are important considerations when investigating circadian and neuroendocrine regulation of immune parameters in animal models [ 2 , 108 ].…”

Section: Findings From Different Animal Speciesmentioning

confidence: 99%

The contribution of sleep to the neuroendocrine regulation of rhythms in human leukocyte traffic

2022

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Twenty-four-hour rhythms in immune parameters and functions are robustly observed phenomena in biomedicine. Here, we summarize the important role of sleep and associated parameters on the neuroendocrine regulation of rhythmic immune cell traffic to different compartments, with a focus on human leukocyte subsets. Blood counts of “stress leukocytes” such as neutrophils, natural killer cells, and highly differentiated cytotoxic T cells present a rhythm with a daytime peak. It is mediated by morning increases in epinephrine, leading to a mobilization of these cells out of the marginal pool into the circulation following a fast, beta2-adrenoceptor-dependent inhibition of adhesive integrin signaling. In contrast, other subsets such as eosinophils and less differentiated T cells are redirected out of the circulation during daytime. This is mediated by stimulation of the glucocorticoid receptor following morning increases in cortisol, which promotes CXCR4-driven leukocyte traffic, presumably to the bone marrow. Hence, these cells show highest numbers in blood at night when cortisol levels are lowest. Sleep adds to these rhythms by actively suppressing epinephrine and cortisol levels. In addition, sleep increases levels of immunosupportive mediators, such as aldosterone and growth hormone, which are assumed to promote T-cell homing to lymph nodes, thus facilitating the initiation of adaptive immune responses during sleep. Taken together, sleep–wake behavior with its unique neuroendocrine changes regulates human leukocyte traffic with overall immunosupportive effects during nocturnal sleep. In contrast, integrin de-activation and redistribution of certain leukocytes to the bone marrow during daytime activity presumably serves immune regulation and homeostasis.

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“…Clear examples of such interactions include the demonstration that muscularis macrophages in the intestine upregulate tissue repair genes, including arginase-1 via β 2 -adrenoceptor stimulation in response to noradrenaline produced by local sympathetic nerves ( Gabanyi et al, 2016 ). Optogenetic activation of sympathetic nerves in the colon was found to reduce expression of MAdCAM1 and ICAM1 on endothelial cells via the β 2 -adrenoceptor, thereby reducing leukocyte recruitment to the colon and ameliorating experimental colitis ( Schiller et al, 2021 ).…”

Section: Neural Control Of Leukocyte Recruitment To Tissuesmentioning

confidence: 99%

Neural control of immune cell trafficking

Mueller

2022

Journal of Experimental Medicine

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Leukocyte trafficking between blood and tissues is an essential function of the immune system that facilitates humoral and cellular immune responses. Within tissues, leukocytes perform surveillance and effector functions via cell motility and migration toward sites of tissue damage, infection, or inflammation. Neurotransmitters that are produced by the nervous system influence leukocyte trafficking around the body and the interstitial migration of immune cells in tissues. Neural regulation of leukocyte dynamics is influenced by circadian rhythms and altered by stress and disease. This review examines current knowledge of neuro–immune interactions that regulate leukocyte migration and consequences for protective immunity against infections and cancer.

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Optogenetic activation of local colonic sympathetic innervations attenuates colitis by limiting immune cell extravasation

Abstract: Highlights d Optogenetic activation of local sympathetic fibers in the colon attenuates colitis d The local sympathetic activation reduces immune cell abundance d Reduction in immune abundance is mediated by a decrease in endothelial MAdCAM-1

Cited by 34 publications

References 93 publications

Transduction of Systemically Administered Adeno-Associated Virus in the Colonic Enteric Nervous System and c-Kit Cells of Adult Mice

Transduction of Systemically Administered Adeno-Associated Virus in the Colonic Enteric Nervous System and c-Kit Cells of Adult Mice

The contribution of sleep to the neuroendocrine regulation of rhythms in human leukocyte traffic

Neural control of immune cell trafficking

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