IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis

Ahsan, Fadhil; Maertzdorf, Jeroen; Guhlich-Bornhof, Ute; Kaufmann, Stefan H. E.; Moura-Alves, Pedro

doi:10.1038/s41598-018-19476-x

Cited by 40 publications

(41 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1a and Supplementary Data 1). As expected, key IL-36 target genes (IL1B, PI3, VNN2, TNFAIP6, SERPINB1) 15 collectively showed a significant up-regulation in cases vs. controls (P=0.019) ( Fig.1b). Of note, the analysis of a publicly available PsV dataset (whole-blood samples obtained from 33 cases vs 44 controls) 16 identified a moderate, but statistically significant, over-expression of the same genes (P=0.001) ( Fig.1b), providing the first indication that IL-36 may have systemic effects in PsV.…”

Section: Expression Profiling Identifies a Type-i Ifn Signature In Gpsupporting

confidence: 77%

Interleukin-36 promotes systemic Type-I IFN responses in severe psoriasis.

Catapano¹,

Vergnano²,

Romano³

et al. 2018

Preprint

View full text Add to dashboard Cite

Psoriasis is an immune-mediated skin disorder associated with severe systemic co-morbidities. Both chronic and acute forms of the disease are characterised by abnormal interleukin (IL)-36 signalling.While the mechanisms whereby IL-36 promotes cutaneous inflammation are well established, its systemic effects have not been investigated. To address this issue, we initially measured leukocyte gene expression in generalised pustular psoriasis, an acute disease variant caused by mutations of the IL-36 receptor antagonist. By undertaking whole-blood and neutrophil RNA-sequencing in affected individuals, we identified a Type-I IFN signature, which correlated with IL-36 signalling up-regulation.We then validated these observations in patients with chronic plaque psoriasis. Finally, we demonstrated that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates Toll-like Receptor (TLR)-9 activation and IFNproduction. This effect was mediated by the induction of PLSCR1, an endosomal TLR-9 transporter. These results define an IL-36/TLR-9/Type-I IFN axis that could be targeted for the treatment of psoriasis co-morbidities.(152 words)

show abstract

Section: Expression Profiling Identifies a Type-i Ifn Signature In Gpsupporting

confidence: 77%

Interleukin-36 promotes systemic Type-I IFN responses in severe psoriasis.

Catapano¹,

Vergnano²,

Romano³

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Although the protective role of IL-36g against M. tuberculosis through regulation of oxysterol and AP expression has been reported (14,15), the underlying mechanisms are not yet fully elucidated. In this study, we showed a novel, autophagyinvolved bactericidal mechanism of IL-36g in human macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…In human PBMCs, in contrast, only APCs but not T cells express IL-36R (13), suggesting the importance of IL-36g in human innate immune regulation. Recently, it was reported that increased IL-36g in macrophages upon M. tuberculosis infection induced several kinds of APs and restricted intracellular M. tuberculosis growth, whereas such effects were attenuated in IL-36R knockdown macrophages (14,15), demonstrating the importance of IL-36g in the control of M. tuberculosis. Therefore, induction of IL-36g expression is important in the host resistance to M. tuberculosis, with unelucidated functional mechanisms.…”

Section: Il-36g Promotes Killing Of Mycobacterium Tuberculosis By Macmentioning

confidence: 99%

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

Gao

Wen

et al. 2019

The Journal of Immunology

View full text Add to dashboard Cite

Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes, remains the leading bacterial cause of enormous morbidity and mortality because of bacterial infections in humans throughout the world. The IL-1 family of cytokines is critical for host resistance to M. tuberculosis. As a newly discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven to play roles in protection against M. tuberculosis infection, the antibacterial mechanisms are poorly understood. In this study, we demonstrated that IL-36γ conferred to human monocyte-derived macrophages bacterial resistance through activation of autophagy as well as induction of WNT5A, a reported downstream effector of IL-1 involved in several inflammatory diseases. Further studies showed that WNT5A could enhance autophagy of monocyte-derived macrophages by inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.

show abstract

“…Indeed, IL-36γ −/− mice exhibited delayed clearance of Streptococcus pneumoniae and Klebsiella pneumoniae in lung infections, decreased Th1 and Th17 cytokine levels, and increased mortality [18]. In Mycobacterium tuberculosis infections, IL-36γ promotes the production of AMPs that limit bacterial growth [13, 26]. In another study, it was found that IL-36R signaling and IL-36α promoted the production of immune mediators and increased influx of neutrophils and monocytes in response to influenza virus infection in the lungs, indicating that the IL-36 cytokines may have distinct functions in response to specific inflammatory stimuli[14].…”

Section: Introductionmentioning

confidence: 99%

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Gardner

Herbst-Kralovetz

2018

Cytokine

View full text Add to dashboard Cite

Herpes simplex virus 2 (HSV-2) causes a persistent, lifelong infection that increases risk for sexually transmitted infection acquisition. Both the lack of a vaccine and the need for chronic suppressive therapies to control infection presents the need to further understand immune mechanisms in response to acute HSV-2 infection. The IL-36 cytokines are recently identified members of the IL-1 family and function as inflammatory mediators at epithelial sites. Here, we first used a well-characterized three-dimensional (3-D) human vaginal epithelial cell (VEC) model to understand the role of IL-36γ in the context of HSV-2 infection. In 3-D VEC, IL-36γ is induced by HSV-2 infection, and pretreatment with exogenous IL-36γ significantly reduced HSV-2 replication. To assess the impact of IL-36γ treatment on HSV-2 disease pathogenesis, we employed a lethal genital infection model. We showed that IL-36γ treatment in mice prior to lethal intravaginal challenge significantly limited vaginal viral replication, delayed disease onset, decreased disease severity, and significantly increased survival. We demonstrated that IL-36γ treatment transiently induced pro-inflammatory cytokines, chemokines, and antimicrobial peptides in murine lower female reproductive tract (FRT) tissue and vaginal lavages. Induction of the chemokines CCL20 and KC in IL-36γ treated mice also corresponded with increased polymorphonuclear (PMN) leukocyte infiltration observed in vaginal smears. Altogether, these studies demonstrate that IL-36γ drives the transient production of immune mediators and promotes PMN recruitment in the vaginal microenvironment that increases resistance to HSV-2 infection and disease. Our data indicate that IL-36γ may participate as a key player in host defense mechanisms against invading pathogens in the FRT.

show abstract

IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis

Cited by 40 publications

References 63 publications

Interleukin-36 promotes systemic Type-I IFN responses in severe psoriasis.

Interleukin-36 promotes systemic Type-I IFN responses in severe psoriasis.

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling

IL-36γ induces a transient HSV-2 resistant environment that protects against genital disease and pathogenesis

Contact Info

Product

Resources

About