title: DNA Sensing via TLR-9 Constitutes a Major Innate Immunity Pathway Activated during Erythema Nodosum Leprosum.
abstract: The chronic course of lepromatous leprosy may be interrupted by acute inflammatory episodes known as erythema nodosum leprosum (ENL). Despite its being a major cause of peripheral nerve damage in leprosy patients, the immunopathogenesis of ENL remains ill-defined. Recognized by distinct families of germline-encoded pattern recognition receptors, endogenous and pathogen-derived nucleic acids are highly immunostimulatory molecules that play a major role in the host defense against infections, autoimmunity, and autoinflammation. The aim of this work was to investigate whether DNA sensing via TLR-9 constitutes a major inflammatory pathway during ENL. Flow cytometry and immunohistochemistry analysis showed significantly higher TLR-9 expression in ENL when compared with nonreactional lepromatous patients, both locally in the skin lesions and in circulating mononuclear cells. The levels of endogenous and pathogen-derived TLR-9 ligands in the circulation of ENL patients were also higher. Furthermore, PBMCs isolated from the ENL patients secreted higher levels of TNF, IL-6, and IL-1β in response to a TLR-9 agonist than those of the nonreactional patients and healthy individuals. Finally, E6446, a TLR-9 synthetic antagonist, was able to significantly inhibit the secretion of proinflammatory cytokines by ENL PBMCs in response to Mycobacterium leprae lysate. Our data strongly indicate that DNA sensing via TLR-9 constitutes a major innate immunity pathway involved in the pathogenesis and evolution of ENL. Thus, the use of TLR-9 antagonists emerges as a potential alternative to more effectively treat ENL aiming to prevent the development of nerve injuries and deformities in leprosy.
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil;
authors.forename: André A
authors.initials: AA
authors.lastname: Dias
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil;
authors.forename: Camila O
authors.initials: CO
authors.lastname: Silva
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil;
authors.forename: João Pedro S
authors.initials: JP
authors.lastname: Santos
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil;
authors.forename: Leonardo R
authors.identifier: 0000-0003-3103-9613
authors.initials: LR
authors.lastname: Batista-Silva
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil;
authors.forename: Chyntia Carolina D
authors.initials: CC
authors.lastname: Acosta
authors.affiliation: Laboratory of Molecular Biology Applied to Mycobacteria, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil; and.
authors.forename: Amanda N B
authors.initials: AN
authors.lastname: Fontes
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil.
authors.forename: Roberta O
authors.initials: RO
authors.lastname: Pinheiro
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil;
authors.forename: Flávio A
authors.initials: FA
authors.lastname: Lara
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Machado
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil.
authors.forename: José Augusto C
authors.initials: JA
authors.lastname: Nery
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil.
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil;
authors.forename: Geraldo M B
authors.initials: GM
authors.lastname: Pereira
authors.affiliation: Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 20045-900, Brazil; cpessola@ioc.fiocruz.br.
authors.forename: Maria Cristina V
authors.initials: MC
authors.lastname: Pessolani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004247:DNA / Q000378:metabolism*; D004893:Erythema Nodosum / Q000276:immunology* / Q000382:microbiology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate; D015440:Leprosy, Lepromatous / Q000276:immunology* / Q000382:microbiology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae / Q000737:chemistry / Q000276:immunology; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*; D055815:Young Adult
chemical_list: C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D004247:DNA