Mycobacterium leprae-induced Insulin-like Growth Factor I attenuates antimicrobial mechanisms, promoting bacterial survival in macrophages.
Mycobacterium leprae (ML), the etiologic agent of leprosy, can subvert macrophage antimicrobial activity by mechanisms that remain only partially understood. In the present study, the participation of hormone insulin-like growth factor I (IGF-I) in this phenomenum was investigated. Macrophages from the dermal lesions of the disseminated multibacillary lepromatous form (LL) of leprosy expressed higher levels of IGF-I than those from the self-limited paucibacillary tuberculoid form (BT). Higher levels of IGF-I secretion by ML-infected macrophages were confirmed in ex vivo and in vitro studies. Of note, the dampening of IGF-I signaling reverted the capacity of ML-infected human and murine macrophages to produce antimicrobial molecules and promoted bacterial killing. Moreover, IGF-I was shown to inhibit the JAK/STAT1-dependent signaling pathways triggered by both mycobacteria and IFN-γ most probably through its capacity to induce the suppressor of cytokine signaling-3 (SOCS3). Finally, these in vitro findings were corroborated by in vivo observations in which higher SOCS3 expression and lower phosphorylation of STAT1 levels were found in LL versus BT dermal lesions. Altogether, our data strongly suggest that IGF-I contributes to the maintenance of a functional program in infected macrophages that suits ML persistence in the host, reinforcing a key role for IGF-I in leprosy pathogenesis.
Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
L R
LR
Batista-Silva
Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
Luciana Silva
LS
Rodrigues
Laboratory of Molecular Parasitology, Carlos Chagas Filho Institute, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, 21940-590, RJ, Brazil.
Aislan de Carvalho
Ade C
Vivarini
Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
Fabrício da Mota Ramalho
Fda M
Costa
Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
Katherine Antunes de
KA
Mattos
Lauro de Souza Lima Institute, Bauru, 17034-971, SP, Brazil.
Maria Renata Sales Nogueira
MR
Costa
Lauro de Souza Lima Institute, Bauru, 17034-971, SP, Brazil.
Patricia Sammarco
PS
Rosa
Leprosy Laboratory, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
T G
TG
Toledo-Pinto
Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
André Alves
AA
Dias
Leprosy Laboratory, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
Danielle Fonseca
DF
Moura
Leprosy Laboratory, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
Euzenir Nunes
EN
Sarno
Laboratory of Molecular Parasitology, Carlos Chagas Filho Institute, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, 21940-590, RJ, Brazil.
Ulisses Gazos
UG
Lopes
Laboratory of Cellular Microbiology, Oswaldo Cruz Institute, Rio de Janeiro, 21040-900, RJ, Brazil.
Maria Cristina Vidal
MC
Pessolani
D000328:Adult; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D007918:Leprosy / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D009166:Mycobacterium leprae / Q000472:pathogenicity*; D050794:STAT1 Transcription Factor / Q000378:metabolism
D050794:STAT1 Transcription Factor; D007334:Insulin-Like Growth Factor I; D053612:Janus Kinases