Abstract
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.
Highlights
Leprosy manifests as a range of clinical forms in correlation with the type of immunological response generated during Mycobacterium leprae (ML) infection
Our results strongly suggest that the endogenous Insulin-like growth factor I (IGF-I) produced by ML-infected macrophages inhibits the host cell antimicrobial mechanisms by blocking JAK/STAT-1-dependent signaling pathways activated in response to mycobacterial infection and IFN-γstimulation
ML-infected macrophages become resistant to IFN-γactivation[8], express higher levels of such scavenger receptors as CD36, SRA, and CD16316, and present a phenotype similar to the one induced in vitro by IL-10, which increases the phagocytic capacity of macrophages and leads to a reduction in bactericidal activity[6]
Summary
The levels of IGF-I expression in dermal lesions of leprosy patients correlate with the outcome of the infection. The inhibition of rIFN-γ-induced iNOS expression by rIGF-I was observed in RAW 264.7 cells transfected with the iNOS promoter-luciferase reporter constructs pTK-3XS (about 68%, p < 0.0001) and pTK-3XNS (~54%, p < 0.0001), as shown in Fig. 3C,D, respectively These data clearly show that IGF-I is able to downregulate IFN-γ-mediated STAT1 activation pathway in RAW macrophages. The accelerated killing of ML observed in IGF-1R knockdown cells positively correlated with the expression of the antimicrobial peptide cathelicidin (2.9 fold higher, p = 0.012) (Fig. 4F) These data indicate that the IGF-I signaling pathway plays a role in bacterial intracellular survival in human macrophages by attenuating the vitamin D-cathelicidin innate immune pathway. Based on our findings, a similar rationale could be applied to leprosy, potentially opening new avenues for novel therapeutic strategies to treat the disease
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