IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB

Victor, Aaron R.; Nalin, Ansel P.; Dong, Wenjuan; McClory, Susan; Min, Wei; Mao, Charlene; Kladney, Raleigh D.; Youssef, Youssef; Chan, Wing Keung; Briercheck, Edward L.; Hughes, Tiffany; Scoville, Steven D.; Pitarresi, Jason R.; Chen, Charlie; Manz, Sarah; Wu, Lai-Chu; Zhang, Jianying; Ostrowski, Michael C.; Freud, Aharon G.; Leone, Gustavo; Caligiuri, Michael A.; Yu, Jianhua

doi:10.4049/jimmunol.1601554

Cited by 79 publications

(53 citation statements)

References 73 publications

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“…S3 F). Unexpectedly, IL-18 was a strong inducer of both c-Maf expression and IFNγ, which supports a pleiotropic role for this cytokine in promoting both type 1 and type 3 features, as reported by others (Bernink et al, 2015;Victor et al, 2017). Together, these trends imply that lineage-relevant cytokines promote c-Maf rather than target its reduction in NKp46 + ILC3s.…”

Section: C-maf Limits Ilc3→ilc1 Plasticitysupporting

confidence: 80%

c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program

Parker

Barrera

Wheaton

et al. 2019

Journal of Experimental Medicine

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CCR6− group 3 innate lymphoid cells (ILC3s) are mediators of intestinal immunity and barrier function that possess the capacity to acquire type 1 effector features and fully convert into ILC1s. The molecular mechanisms governing such plasticity are undefined. Here, we identified c-Maf as an essential regulator of ILC3 homeostasis and plasticity that limits physiological ILC1 conversion. Phenotypic analysis of effector status in Maf-deficient CCR6− ILC3s, coupled with evaluation of global changes in transcriptome, chromatin accessibility, and transcription factor motif enrichment, revealed that c-Maf enforces ILC3 identity. c-Maf promoted ILC3 accessibility and supported RORγt activity and expression of type 3 effector genes. Conversely, c-Maf antagonized type 1 programming, largely through restraint of T-bet expression and function. Mapping of the dynamic changes in chromatin landscape accompanying CCR6− ILC3 development and ILC1 conversion solidified c-Maf as a gatekeeper of type 1 regulatory transformation and a controller of ILC3 fate.

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Section: C-maf Limits Ilc3→ilc1 Plasticitysupporting

confidence: 80%

c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program

Parker

Barrera

Wheaton

et al. 2019

Journal of Experimental Medicine

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“…While we revealed a role for ATF3 in the IBD gene network of IL-22-STAT3, a function for ATF3 in IL-6-STAT3 or even IL-23-STAT3 activation in Th17 cell network has also been observed in our study. As an upstream regulator, ATF3 could suppress IL-6 transcription or even IL-22 transcription via NF-kB ( 18 , 64 ). However, as a downstream regulator, we showed ATF3 is required to relay IL-6 and IL-22 signaling for the induction of STAT3 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

ATF3 Sustains IL-22-Induced STAT3 Phosphorylation to Maintain Mucosal Immunity Through Inhibiting Phosphatases

Glal

Sudhakar

et al. 2018

Front. Immunol.

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In gut epithelium, IL-22 transmits signals through STAT3 phosphorylation (pSTAT3) which provides intestinal immunity. Many components in the IL-22-pSTAT3 pathway have been identified as risk factors for inflammatory bowel disease (IBD) and some of them are considered as promising therapeutic targets. However, new perspectives are still needed to understand IL-22-pSTAT3 signaling for effective clinical interventions in IBD patients. Here, we revealed activating transcription factor 3 (ATF3), recently identified to be upregulated in patients with active IBD, as a crucial player in the epithelial IL-22-pSTAT3 signaling cascade. We found ATF3 is central to intestinal homeostasis and provides protection during colitis. Loss of ATF3 led to decreased crypt numbers, more shortened colon length, impaired ileal fucosylation at the steady state, and lethal disease activity during DSS-induced colitis which can be effectively ameliorated by rectal transplantation of wild-type colonic organoids. Epithelial stem cells and Paneth cells form a niche to orchestrate epithelial regeneration and host-microbe interactions, and IL-22-pSTAT3 signaling is a key guardian for this niche. We found ATF3 is critical for niche maintenance as ATF3 deficiency caused compromised stem cell growth and regeneration, as well as Paneth cell degeneration and loss of anti-microbial peptide (AMP)-producing granules, indicative of malfunction of Paneth/stem cell network. Mechanistically, we found IL-22 upregulates ATF3, which is required to relay IL-22 signaling leading to STAT3 phosphorylation and subsequent AMP induction. Intriguingly, ATF3 itself does not act on STAT3 directly, instead ATF3 regulates pSTAT3 by negatively targeting protein tyrosine phosphatases (PTPs) including SHP2 and PTP-Meg2. Furthermore, we identified ATF3 is also involved in IL-6-mediated STAT3 activation in T cells and loss of ATF3 leads to reduced capacity of Th17 cells to produce their signature cytokine IL-22 and IL-17A. Collectively, our results suggest that via IL-22-pSTAT3 signaling in the epithelium and IL-6-pSTAT3 signaling in Th17 cells, ATF3 mediates a cross-regulation in the barrier to maintain mucosal homeostasis and immunity.

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“…IL-18 upregulates SGK1 expression and augments phosphate-induced SGK1 expression in VSMCs. Excessive SGK1 is sufficient to promote osteo-/chondrogenic transdifferentiation of VSMCs via NF-kB activation [ 58 ] and NF-kB activity can be induced by IL-18 [ 24 , 42 , 50 , 60 ]. SGK1 similarly plays a key role in vascular inflammation during atherogenesis via activation of NF-kB [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

SGK1-dependent stimulation of vascular smooth muscle cell osteo-/chondrogenic transdifferentiation by interleukin-18

Schelski

Luong

Läng

et al. 2019

Pflugers Arch - Eur J Physiol

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The serum- and glucocorticoid-inducible kinase 1 (SGK1) is a key regulator of osteo-/chondrogenic transdifferentiation and subsequent calcification of vascular smooth muscle cells (VSMCs). The phenotypical transdifferentiation of VSMCs is associated with increased interleukin-18 (IL-18) levels and generalized inflammation. Therefore, the present study investigated the possible involvement of SGK1 in IL-18-induced vascular calcification. Experiments were performed in primary human aortic smooth muscle cells (HAoSMCs) treated with recombinant human IL-18 protein in control or high phosphate conditions and following SGK1 knockdown by siRNA or pharmacological inhibition of SGK1, PI3K, and PDK1. As a result, IL-18 treatment increased SGK1 mRNA and protein expression in HAoSMCs. IL-18 upregulated SGK1 mRNA expression in a dose-dependent manner. This effect was paralleled by upregulation of the mRNA expression of MSX2 and CBFA1 , osteogenic transcription factors, and of tissue-nonspecific alkaline phosphatase ( ALPL ), an osteogenic enzyme, as markers of increased osteo-/chondrogenic transdifferentiation. Phosphate treatment increased SGK1 and osteogenic markers mRNA expression as well as ALPL activity and induced calcification of HAoSMCs, all effects significantly augmented by additional treatment with IL-18. Conversely, silencing of SGK1 or cotreatment with the SGK1 inhibitor EMD638683 blunted the effects of IL-18 on osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. The procalcific effects of IL-18 were similarly suppressed in the presence of PI3K or PDK1 inhibitors. In conclusion, SGK1 expression is upregulated by IL-18 in VSMCs and SGK1 participates in the intracellular signaling of IL-18-induced osteo-/chondrogenic transdifferentiation of VSMCs. Thus, SGK1 may serve as therapeutic target to limit the progression of medial vascular calcification during vascular inflammation.

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IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB

Cited by 79 publications

References 73 publications

c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program

c-Maf regulates the plasticity of group 3 innate lymphoid cells by restraining the type 1 program

ATF3 Sustains IL-22-Induced STAT3 Phosphorylation to Maintain Mucosal Immunity Through Inhibiting Phosphatases

SGK1-dependent stimulation of vascular smooth muscle cell osteo-/chondrogenic transdifferentiation by interleukin-18

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