Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cells
Abstract Background Huntington’s disease (HD) is caused by the expression of a mutated variant of Huntingtin (mHtt), which results in the complex pathology characterized by a defective function of the nervous system and altered inflammatory responses. While the neuronal effects of mHtt expression ha...
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01758-9 |
| _version_ | 1818137032324546560 |
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| author | Marian Jesabel Pérez-Rodríguez Alfredo Ibarra-Sánchez Abraham Román-Figueroa Francisca Pérez-Severiano Claudia González-Espinosa |
| author_facet | Marian Jesabel Pérez-Rodríguez Alfredo Ibarra-Sánchez Abraham Román-Figueroa Francisca Pérez-Severiano Claudia González-Espinosa |
| author_sort | Marian Jesabel Pérez-Rodríguez |
| collection | DOAJ |
| description | Abstract Background Huntington’s disease (HD) is caused by the expression of a mutated variant of Huntingtin (mHtt), which results in the complex pathology characterized by a defective function of the nervous system and altered inflammatory responses. While the neuronal effects of mHtt expression have been extensively studied, its effects on the physiology of immune cells have not been fully described. Mast cells (MCs) are unique tissue-resident immune cells whose activation has been linked to protective responses against parasites and bacteria, but also to deleterious inflammatory allergic reactions and, recently, to neurodegenerative diseases. Methods Bone marrow-derived mast cells (BMMCs) were obtained from wild-type (WT-) and mHtt-expressing (R6/1) mice to evaluate the main activation parameters triggered by the high-affinity IgE receptor (FcεRI) and the Toll-like receptor (TLR) 4. Degranulation was assessed by measuring the secretion of β-hexosaminidase, MAP kinase activation was detected by Western blot, and cytokine production was determined by RT-PCR and ELISA. TLR-4 receptor and Htt vesicular trafficking was analyzed by confocal microscopy. In vivo, MC-deficient mice (c-Kit Wsh/Wsh ) were intraperitonally reconstituted with WT or R6/1 BMMCs and the TLR4-induced production of the tumor necrosis factor (TNF) was determined by ELISA. A survival curve of mice treated with a sub-lethal dose of bacterial lipopolysaccharide (LPS) was constructed. Results R6/1 BMMCs showed normal β-hexosaminidase release levels in response to FcεRI, but lower cytokine production upon LPS stimulus. Impaired TLR4-induced TNF production was associated to the lack of intracellular dynamin-dependent TLR-4 receptor trafficking to perinuclear regions in BMMCs, a diminished ERK1/2 and ELK-1 phosphorylation, and a decrease in c-fos and TNF mRNA accumulation. R6/1 BMMCs also failed to produce TLR4-induced anti-inflammatory cytokines (like IL-10 and TGF-β). The detected defects were also observed in vivo, in a MCs-dependent model of endotoxemia. R6/1 and c-Kit Wsh/Wsh mice reconstituted with R6/1 BMMCs showed a decreased TLR4-induced TNF production and lower survival rates to LPS challenge than WT mice. Conclusions Our data show that mHtt expression causes an impaired production of pro- and anti-inflammatory mediators triggered by TLR-4 receptor in MCs in vitro and in vivo, which could contribute to the aberrant immunophenotype observed in HD. |
| first_indexed | 2024-12-11T09:49:51Z |
| format | Article |
| id | doaj.art-20ed624ddb5a4a639fa6a26d0b3dac1f |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-11T09:49:51Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-20ed624ddb5a4a639fa6a26d0b3dac1f2022-12-22T01:12:26ZengBMCJournal of Neuroinflammation1742-20942020-03-0117111810.1186/s12974-020-01758-9Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cellsMarian Jesabel Pérez-Rodríguez0Alfredo Ibarra-Sánchez1Abraham Román-Figueroa2Francisca Pérez-Severiano3Claudia González-Espinosa4Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPNDepartamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPNDepartamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPNLaboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPNAbstract Background Huntington’s disease (HD) is caused by the expression of a mutated variant of Huntingtin (mHtt), which results in the complex pathology characterized by a defective function of the nervous system and altered inflammatory responses. While the neuronal effects of mHtt expression have been extensively studied, its effects on the physiology of immune cells have not been fully described. Mast cells (MCs) are unique tissue-resident immune cells whose activation has been linked to protective responses against parasites and bacteria, but also to deleterious inflammatory allergic reactions and, recently, to neurodegenerative diseases. Methods Bone marrow-derived mast cells (BMMCs) were obtained from wild-type (WT-) and mHtt-expressing (R6/1) mice to evaluate the main activation parameters triggered by the high-affinity IgE receptor (FcεRI) and the Toll-like receptor (TLR) 4. Degranulation was assessed by measuring the secretion of β-hexosaminidase, MAP kinase activation was detected by Western blot, and cytokine production was determined by RT-PCR and ELISA. TLR-4 receptor and Htt vesicular trafficking was analyzed by confocal microscopy. In vivo, MC-deficient mice (c-Kit Wsh/Wsh ) were intraperitonally reconstituted with WT or R6/1 BMMCs and the TLR4-induced production of the tumor necrosis factor (TNF) was determined by ELISA. A survival curve of mice treated with a sub-lethal dose of bacterial lipopolysaccharide (LPS) was constructed. Results R6/1 BMMCs showed normal β-hexosaminidase release levels in response to FcεRI, but lower cytokine production upon LPS stimulus. Impaired TLR4-induced TNF production was associated to the lack of intracellular dynamin-dependent TLR-4 receptor trafficking to perinuclear regions in BMMCs, a diminished ERK1/2 and ELK-1 phosphorylation, and a decrease in c-fos and TNF mRNA accumulation. R6/1 BMMCs also failed to produce TLR4-induced anti-inflammatory cytokines (like IL-10 and TGF-β). The detected defects were also observed in vivo, in a MCs-dependent model of endotoxemia. R6/1 and c-Kit Wsh/Wsh mice reconstituted with R6/1 BMMCs showed a decreased TLR4-induced TNF production and lower survival rates to LPS challenge than WT mice. Conclusions Our data show that mHtt expression causes an impaired production of pro- and anti-inflammatory mediators triggered by TLR-4 receptor in MCs in vitro and in vivo, which could contribute to the aberrant immunophenotype observed in HD.http://link.springer.com/article/10.1186/s12974-020-01758-9HuntingtinMast cellsTLR-4SignalingIntracellular receptor trafficking |
| spellingShingle | Marian Jesabel Pérez-Rodríguez Alfredo Ibarra-Sánchez Abraham Román-Figueroa Francisca Pérez-Severiano Claudia González-Espinosa Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cells Journal of Neuroinflammation Huntingtin Mast cells TLR-4 Signaling Intracellular receptor trafficking |
| title | Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cells |
| title_full | Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cells |
| title_fullStr | Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cells |
| title_full_unstemmed | Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cells |
| title_short | Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cells |
| title_sort | mutant huntingtin affects toll like receptor 4 intracellular trafficking and cytokine production in mast cells |
| topic | Huntingtin Mast cells TLR-4 Signaling Intracellular receptor trafficking |
| url | http://link.springer.com/article/10.1186/s12974-020-01758-9 |
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