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NAD⁺-boosting molecules suppress mast cell degranulation and anaphylactic responses in mice.

ABSTRACT: Nicotinamide adenine dinucleotide (NAD⁺) acts as a cofactor for multiple biological processes. While previous research has revealed that the NAD⁺ declines associated with aging contributes to an impairment of immune cells, its role in mast cell function, especially in response to an anaphylactic condition, has remained unexplored. We tested whether the restoration of cellular NAD⁺ concentration by the supplementation of NAD⁺ boosting molecules prevented mast cell degranulation and anaphylactic responses. Methods: Bone marrow derived mast cells (BMMCs) and human cord blood derived mast cells were treated with NAD⁺ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), and FcεRI downstream signaling was assessed. Animal models of passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA) were used to investigate the effects of NAD⁺ precursors in the anaphylactic responses of mice. Results: Treatment of murine BMMCs and human cord blood derived mast cells with NAD⁺ precursors repressed intracellular signaling downstream of FcεRI, as well as the release of inflammatory cytokines and lipid mediators. The intraperitoneal administration of NMN or NR also markedly attenuated IgE-mediated anaphylactic responses in mouse models of PSA and PCA. These beneficial effects of NAD⁺ precursors, however, were attenuated in mast cell-specific Sirt6 knockout mice, indicating a Sirt6 dependency for their action. Conclusion: NAD⁺ precursors may serve as an effective therapeutic strategy that limits mast cell-mediated anaphylactic responses.

SUBMITTER: Kim HW

PROVIDER: S-EPMC9065190 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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NAD+-boosting molecules suppress mast cell degranulation and anaphylactic responses in mice.

Kim Hyun-Woo HW Ryoo Ga-Hee GH Jang Hyun-Young HY Rah So-Young SY Lee Dong Hyun DH Kim Do-Kyun DK Bae Eun Ju EJ Park Byung-Hyun BH

Theranostics 20220411 7

Nicotinamide adenine dinucleotide (NAD+) acts as a cofactor for multiple biological processes. While previous research has revealed that the NAD+ declines associated with aging contributes to an impairment of immune cells, its role in mast cell function, especially in response to an anaphylactic condition, has remained unexplored. We tested whether the restoration of cellular NAD+ concentration by the supplementation of NAD+ boosting molecules prevente ...[more]

PMID: 35547746

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Project description:Cancer pain induced by pancreatic carcinoma is one of the most common symptoms and is difficult to endure, especially in the advanced stage. Evidence suggests that mast cells are recruited and degranulate in enteric disease-related visceral hypersensitivity. However, whether mast cells promote the visceral pain induced by pancreatic carcinoma remains unclear. Here, using toluidine blue staining and western blotting, we observed that mast cells were dramatically recruited to tissues surrounding pancreatic carcinoma, but not inside the carcinoma in patients with severe visceral pain. The levels of mast cell degranulation products, including tryptase, histamine, and nerve growth factor, were significantly increased in pericarcinoma tissues relative to their levels in normal controls, as evidenced by enzyme-linked immunosorbent assay. We determined that systemic administration of mast cell secretagogue compound 48/80 exacerbated pancreatic carcinoma-induced visceral hypersensitivity in a male BALB/c nude mouse model as assessed by measuring the hunching behavior scores and mechanical withdrawal response frequency evoked by von Frey stimulation. In contrast, the mast cell stabilizer ketotifen dose-dependently alleviated pancreatic cancer pain. In addition, we observed incomplete development of abdominal mechanical hyperalgesia and hunching behavior in mast cell-deficient mice with pancreatic carcinoma. However, ketotifen did not further attenuate visceral hypersensitivity in mast cell-deficient mice with carcinoma. Finally, we confirmed that intraplantar injection of pericarcinoma supernatants from BALB/c nude mice but not mast cell-deficient mice caused acute somatic nociception. In conclusion, our findings suggest that mast cells contribute to pancreatic carcinoma-induced visceral hypersensitivity through enrichment and degranulation in pericarcinoma tissues. The inhibition of mast cell degranulation may be a potential strategy for the therapeutic treatment of pancreatic carcinoma-induced chronic visceral pain.

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NAD⁺-boosting molecules suppress mast cell degranulation and anaphylactic responses in mice.

Publications

NAD<sup>+</sup>-boosting molecules suppress mast cell degranulation and anaphylactic responses in mice.

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