Article ; Online: DNA Sensing via TLR-9 Constitutes a Major Innate Immunity Pathway Activated during Erythema Nodosum Leprosum.
Journal of immunology (Baltimore, Md. : 1950)
2016 Volume 197, Issue 5, Page(s) 1905–1913
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 ... ...
| 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. |
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| MeSH term(s) | Adult ; Aged ; Aged, 80 and over ; DNA/metabolism ; Erythema Nodosum/immunology ; Erythema Nodosum/microbiology ; Female ; Flow Cytometry ; Humans ; Immunity, Innate ; Leprosy, Lepromatous/immunology ; Leprosy, Lepromatous/microbiology ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/microbiology ; Male ; Middle Aged ; Mycobacterium leprae/chemistry ; Mycobacterium leprae/immunology ; Signal Transduction ; Toll-Like Receptor 9/immunology ; Toll-Like Receptor 9/metabolism ; Young Adult | ||||||||||
| Chemical Substances | TLR9 protein, human ; Toll-Like Receptor 9 ; DNA (9007-49-2) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2016-09-01 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article | ||||||||||
| ZDB-ID | 3056-9 | ||||||||||
| ISSN | 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381 | ||||||||||
| ISSN (online) | 1550-6606 | ||||||||||
| ISSN | 0022-1767 ; 1048-3233 ; 1047-7381 | ||||||||||
| DOI | 10.4049/jimmunol.1600042 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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