Dataset Information

Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus.

ABSTRACT: Up to 60% of patients with systemic lupus erythematosus (SLE) experience autonomic symptom. Sympathetic nervous system damage can cause dysfunction of the bone marrow that activates inflammatory cells, potentially causing multiple organ damage. We hypothesized that sympathetic nervous system damage would induce bone marrow dysfunction with multiple organ damage in SLE, and that multiple organ damage could be improved by therapy targeting the nervous system. Here, we showed that damage to autonomic nerves and Schwann cells occurred in the bone marrow and central nervous system of SLE model mice. A neurotoxic drug increased mortality and induced severe neuropathy and multiple organ damage, while a neuroprotective drug prevented multiple organ damage. The administration of bone marrow-derived mesenchymal stromal cells (BMSCs) cultured on a 3-dimensional fiber scaffold improved bone marrow neuropathy, skin lesions, kidney function, and mortality. Our results reveal that bone marrow neuropathy influence multiple organ damage associated with SLE, and improvement of bone marrow neuropathy by intrathecal injection of BMSC may be a target for SLE multiple-organ damage.

SUBMITTER: Saito Y

PROVIDER: S-EPMC9216504 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus.

Saito Yuki Y Miyajima Maki M Yamamoto Sena S Miura Norihiro N Sato Tsukasa T Kita Arisa A Ijima Shogo S Fujimiya Mineko M Chikenji Takako S TS

Stem cells translational medicine 20220601 6

Up to 60% of patients with systemic lupus erythematosus (SLE) experience autonomic symptom. Sympathetic nervous system damage can cause dysfunction of the bone marrow that activates inflammatory cells, potentially causing multiple organ damage. We hypothesized that sympathetic nervous system damage would induce bone marrow dysfunction with multiple organ damage in SLE, and that multiple organ damage could be improved by therapy targeting the nervous system. Here, we showed that damage to autonom ...[more]

PMID: 35466994

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Project description:ObjectiveGasdermin D (GSDMD) is the key executioner of an inflammatory cell death mechanism known as pyroptosis. Recent reports have also implicated GSDMD in other mechanisms of cell death, including apoptosis, necroptosis, and NETosis. Given the role of dysregulated cell death in autoimmune syndromes such as systemic lupus erythematosus (SLE), this study was undertaken in a murine lupus model to investigate whether GSDMD plays a pathogenic role in systemic autoimmunity by promoting inflammatory cell death, leading to increased generation of nuclear autoantigens and autoantibodies.MethodsAn imiquimod-induced model of SLE was tested in GSDMD-/- mice (n = 30), with wild-type (WT) mice as controls (n = 34), on a C57BL/6 background. At the time of euthanasia, the mice were examined for serum autoantibodies, immune complex deposition, organ inflammation, immune dysregulation, and type I interferon responses. A model of pristane-induced lung injury in GSDMD-/- mice (n = 7), with WT mice as controls (n = 10), was used to confirm the pulmonary phenotype. Regulation of various mechanisms of cell death by GSDMD was investigated in the mice.ResultsUnexpectedly, GSDMD-/- mice developed enhanced mortality, more severe renal and pulmonary inflammation, and exacerbated autoantibody production in response to imiquimod. Pulmonary involvement was also more severe in the absence of GSDMD in mice with pristane-induced lung injury. Compared to WT mice, lack of GSDMD was associated with increased levels of circulating nuclear autoantigens (P < 0.01), anti-double-stranded DNA autoantibodies (P < 0.01), tissue immune complex deposition (P < 0.05), expansion of myeloid cell subsets (P < 0.05), and enhanced B cell activation and plasma cell differentiation (P = 0.001). Moreover, in the absence of GSDMD, enhanced autoantigen generation was associated with increased local induction of cell death in vivo.ConclusionGSDMD negatively regulates autoantigen generation and immune dysregulation in response to tissue injury and may play previously unappreciated protective roles in systemic autoimmunity.

Dataset Information

Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus.

Publications

Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus.

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