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Med."],"abstract":"<jats:p>In leprosy patients, acute inflammatory episodes, known as erythema nodosum leprosum (ENL), are responsible for high morbidity and tissue damage that occur during the course of <jats:italic>Mycobacterium leprae<\/jats:italic> infection. In a previous study, we showed evidence implicating DNA-sensing <jats:italic>via<\/jats:italic> TLR9 as an important inflammatory pathway in ENL. A likely important consequence of TLR9 pathway activation is the production of type I interferons (IFN-I) by plasmacytoid dendritic cells (pDCs), also implicated in the pathogenesis of several chronic inflammatory diseases. In this study, we investigated whether the IFN-I pathway is activated during ENL. Blood samples and skin lesions from multibacillary patients diagnosed with ENL were collected and the expression of genes of the IFN-I pathway and interferon-stimulated genes were compared with samples collected from non-reactional multibacillary (NR) patients. Whole blood RNAseq analysis suggested higher activation of the IFN-I pathway in ENL patients, confirmed by RT-qPCR. Likewise, significantly higher mRNA levels of IFN-I-related genes were detected in ENL skin biopsies when compared to NR patient lesions. During thalidomide administration, the drug of choice for ENL treatment, a decrease in the mRNA and protein levels of some of these genes both in the skin and blood was observed. Indeed, <jats:italic>in vitro<\/jats:italic> assays showed that thalidomide was able to block the secretion of IFN-I by peripheral blood mononuclear cells in response to <jats:italic>M. leprae<\/jats:italic> sonicate or CpG-A, a TLR9 ligand. Finally, the decreased frequencies of peripheral pDCs in ENL patients, along with the higher TLR9 expression in ENL pDCs and the enrichment of CD123<jats:sup>+<\/jats:sup> cells in ENL skin lesions, suggest the involvement of these cells as IFN-I producers in this type of reaction. Taken together, our data point to the involvement of the pDC\/type I IFN pathway in the pathogenesis of ENL, opening new avenues in identifying biomarkers for early diagnosis and new therapeutic targets for the better management of this reactional episode.<\/jats:p>","DOI":"10.3389\/fmed.2022.899998","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T12:50:03Z","timestamp":1654519803000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The Type I Interferon Pathway Is Upregulated in the Cutaneous Lesions and Blood of Multibacillary Leprosy Patients With Erythema Nodosum Leprosum"],"prefix":"10.3389","volume":"9","author":[{"given":"Thabatta Leal Silveira Andrezo","family":"Rosa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayara 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