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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 (Fc\u03b5RI) and the Toll-like receptor (TLR) 4. Degranulation was assessed by measuring the secretion of \u03b2-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 (<jats:italic>c<\/jats:italic>-<jats:italic>Kit<\/jats:italic><jats:sup><jats:italic>Wsh\/Wsh<\/jats:italic><\/jats:sup>) 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>R6\/1 BMMCs showed normal \u03b2-hexosaminidase release levels in response to Fc\u03b5RI, 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<jats:italic>c<\/jats:italic>-<jats:italic>fos<\/jats:italic>and TNF mRNA accumulation. R6\/1 BMMCs also failed to produce TLR4-induced anti-inflammatory cytokines (like IL-10 and TGF-\u03b2). The detected defects were also observed in vivo, in a MCs-dependent model of endotoxemia. R6\/1 and<jats:italic>c<\/jats:italic>-<jats:italic>Kit<\/jats:italic><jats:sup><jats:italic>Wsh\/Wsh<\/jats:italic><\/jats:sup>mice reconstituted with R6\/1 BMMCs showed a decreased TLR4-induced TNF production and lower survival rates to LPS challenge than WT mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12974-020-01758-9","type":"journal-article","created":{"date-parts":[[2020,3,27]],"date-time":"2020-03-27T18:03:12Z","timestamp":1585332192000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Mutant Huntingtin affects toll-like receptor 4 intracellular trafficking and cytokine production in mast cells"],"prefix":"10.1186","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0383-0320","authenticated-orcid":false,"given":"Marian Jesabel","family":"P\u00e9rez-Rodr\u00edguez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1195-1808","authenticated-orcid":false,"given":"Alfredo","family":"Ibarra-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6306-6803","authenticated-orcid":false,"given":"Abraham","family":"Rom\u00e1n-Figueroa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2840-7991","authenticated-orcid":false,"given":"Francisca","family":"P\u00e9rez-Severiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7332-3829","authenticated-orcid":false,"given":"Claudia","family":"Gonz\u00e1lez-Espinosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,27]]},"reference":[{"key":"1758_CR1","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nrneurol.2014.24","volume":"10","author":"CA Ross","year":"2014","unstructured":"Ross CA, Aylward EH, Wild EJ, Langbehn DR, Long JD, Warner JH, et al. 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