A role for interleukin‐17A in modulating intracellular survival of Mycobacterium bovis bacillus Calmette–Guérin in murine macrophages

Abstract

SummaryInterleukin 17A IL-17A is a crucial immunomodulator in various chronic immunological diseases including rheumatoid arthritis and inflammatory bowel disease. The cytokine has also been demonstrated to control the pathogenesis of the Mycobacterium tuberculosis by dysregulating production of cytokines and chemokines and promoting granuloma formation. Whether IL-17A regulates innate defence mechanisms of macrophages in response to mycobacterial infection remains to be elucidated. In the current report, we investigated the effects of IL-17A on modulating the intracellular survival of Mycobacterium bovis bacillus Calmette-Gu erin (BCG) in RAW264.7 murine macrophages. We observed that IL-17A pretreatment for 24 hr was able to synergistically enhance BCG-induced nitric oxide (NO) production and inducible nitric oxide synthase expression in dose-and time-dependent manners. We further delineated the mechanisms involved in this synergistic reaction. IL-17A was found to specifically enhanced BCG-induced phosphorylation of Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. By using a specific JNK inhibitor (SP600125), we found that the production of NO in BCG-infected macrophages was significantly suppressed. Taken together, we confirmed the involvement of the JNK pathway in IL-17A-enhanced NO production in BCG-infected macrophages. We further demonstrated that IL-17A significantly enhanced the clearance of intracellular BCG by macrophages through an NO-dependent killing mechanism. In conclusion, our study revealed an anti-mycobacterial role of IL-17A through priming the macrophages to produce NO in response to mycobacterial infection.

Cytotoxic effector functions of T cells are not required for protective immunity against fatal Rickettsia typhi infection in a murine model of infection: Role of TH1 and TH17 cytokines in protection and pathology

“…muridarum [ 73 ]. In line with these findings, IL-17A was found to promote the expression of iNOS and the release of NO by macrophages infected with Mycobacterium bovis bacillus Calmette-Guerin (BCG) [ 74 ]. In addition, IL-17A directly inhibits the growth of the intracellular parasite Trypanosoma ( T .)…”

Immune response against rickettsiae: lessons from murine infection models

“…IL-17A/F induce the expression of inflammatory cyokines such as TNFα, IL-1β and IL-6 in tissue cells and MΦ [ 102 – 106 ] and of antimicrobial peptides in tissue cells in concert with IL-22 [ 107 , 108 ]. Moreover, IL-17A has been shown to promote the expression of iNOS and the release of NO by MΦ infected with Mycobacterium bovis bacillus Calmette-Guerin (BCG) [ 109 ] and to inhibit the growth of intracellular parasites such as Chlamydia muridarum in lung epithelial cells and MΦ in vitro in an iNOS-dependent manner [ 110 ] and of Trypanosoma cruzi in infected MΦ in vitro which is mediated via the activation of the NAPDH oxidase [ 111 ]. This enzyme produces superoxide and other ROS that mediate killing of intracellular pathogens in MΦ and neutrophils similar to NO [ 112 ].…”

Transcriptional analysis of human peripheral blood mononuclear cells stimulated by Mycobacterium tuberculosis antigen

“…IL-17 is secreted by Th17 cells, a subset of CD4 + T lymphocytes. IL-17A enhances macrophage clearance of intracellular Mycobacterium via a no-dependent killing mechanism and enhances explicitly BCG-induced JAK-STAT pathway phosphorylation in macrophages ( Gu et al., 2013 ; Ling et al., 2013 ). Pai and Rodrigues ( Pai and Rodrigues, 2015 ) identify the indirect signs of Mtb exposure using the IFN-γ release test, suggesting that there is a cellular immune response to Mtb.…”