| Author | Ávila, Thiago Vinicius | |
| Author | Menezes-Garcia, Zélia | |
| Author | Arifa, Raquel Duque do Nascimento | |
| Author | Soriani, Frederico Marianetti | |
| Author | Machado, Alexandre de Magalhães Vieira | |
| Author | Teixeira, Mauro Martins | |
| Author | Fagundes, Caio Tavares | |
| Author | Souza, Daniele G | |
| Access date | 2023-05-11T17:24:10Z | |
| Available date | 2023-05-11T17:24:10Z | |
| Document date | 2022 | |
| Citation | ÁVILA, Thiago Vinicius et al. Mitochondrial DNA as a Possible Ligand for TLR9 in Irinotecan-induced Small Intestinal Mucositis. Immunol Invest., v. 51, n. 6, p. 1756-1771, 2022. doi: 10.1080/08820139.2022.2026379. | en_US |
| ISSN | 0882-0139 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/58331 | |
| Language | eng | en_US |
| Publisher | Informa Healthcare | en_US |
| Rights | restricted access | |
| Title | Mitochondrial DNA as a Possible Ligand for TLR9 in Irinotecan-induced Small Intestinal Mucositis | en_US |
| Type | Article | |
| Abstract | Cancer chemotherapy and radiotherapy may result in mucositis characterized by stem cell damage and inflammation in the gastrointestinal tract. The molecular mechanisms underlying this pathology remain unknown. Based on the assumption that mitochondrial CPG-DNA (mtDNA) released and sensed by TLR9 could underlie mucositis pathology, we analyzed the mtDNA levels in sera as well as inflammatory and disease parameters in the small intestine from wild-type (WT) and TLR9-deficient mice (TLR9-/-) in an experimental model of intestinal mucositis induced by irinotecan. Additionally, we verified the ability of WT and TLR9-/- macrophages to respond to CpG-DNA in vitro. WT mice injected with irinotecan presented a progressive increase in mtDNA in the serum along with increased hematocrit, shortening of small intestine length, reduction of intestinal villus:crypt ratio and increased influx of neutrophils, which were followed by higher expression of Nlrp3 and Casp1 mRNA and increased IL-1β levels in the ileum when compared to vehicle-injected mice. TLR9-deficient mice were protected in all these parameters when compared to WT mice. Furthermore, TLR9 was required for the production of IL-1β and NO after macrophage stimulation with CpG-DNA. Overall, our findings show that the amount of circulating free CpG-DNA is increased upon chemotherapy and that TLR9 activation is important for NLRP3 inflammasome transcription and further IL-1β release, playing a central role in the development of irinotecan-induced intestinal mucositis. We suggest that TLR9 antagonism may be a new therapeutic strategy for limiting irinotecan-induced intestinal inflammation. | en_US |
| Affilliation | Department of Pharmacology. Federal of Juiz de Fora University. Juiz de Fora, MG, Brazil. | en_US |
| Affilliation | Department of Microbiology and Biochemistry. The University of Texas Southwestern Medical Center. Dallas, Texas, USA. | en_US |
| Affilliation | Laboratório de Interação Microorganismo-Hospedeiro. Department de Microbiology. Federal of Minas Gerais University. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Department de Genetics, Ecology and Evolution. Federal of Minas Gerais University. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Department of Biochemistry and Immunology. Federal of Minas Gerais University. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Laboratório de Interação Microorganismo-Hospedeiro. Department de Microbiology. Federal of Minas Gerais University. Belo Horizonte, MG, Brazil. | en_US |
| Affilliation | Laboratório de Interação Microorganismo-Hospedeiro. Department de Microbiology. Federal of Minas Gerais University. Belo Horizonte, MG, Brazil. | en_US |
| Subject | Intestinal mucositis | en_US |
| Subject | mitochondrial DNA | en_US |
| Subject | toll-like receptor 9 | en_US |
| Embargo date | 2099-12-31 | |
