Emerging roles for IL-11 in inflammatory diseases

Fung, Ka Yee; Louis, Cynthia; Metcalfe, Riley D.; Kosasih, Clara C.; Wicks, Ian P.; Griffin, Michael D. W.; Putoczki, Tracy L.

doi:10.1016/j.cyto.2021.155750

Cited by 46 publications

(59 citation statements)

References 149 publications

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“…Although additional evidence is needed to establish the response to IL-11 as a new molecular mechanism involved in GCA, the potential role that might play in the active state of the disease is intriguing. IL11, a member of the IL-6 family, has been implicated in a range of disease pathologies by exerting diverse immunological roles 33. On the one hand, IL11 inhibits activated macrophages by blocking NF-κB translocation,34 however, several studies have described a proinflammatory function.…”

Section: Discussionmentioning

confidence: 99%

Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids

Estupiñán-Moreno

Ortiz-Fernández

et al. 2022

Ann Rheum Dis

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ObjectivesGiant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis.MethodsWe performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls.ResultsWe identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2.ConclusionOur results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment.

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Section: Discussionmentioning

confidence: 99%

Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids

Estupiñán-Moreno

Ortiz-Fernández

et al. 2022

Ann Rheum Dis

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“…IL11 activates STAT3 in a number of cell types, including fibroblasts [12,18,26,27]. While the role of IL11 in STAT3 activation appears unrelated to fibrogenesis [7], we hypothesized that the early activation of STAT3 from following IL11 exposure might lead to a STAT3-driven transcriptional response.…”

Section: Resultsmentioning

confidence: 99%

“…There is a large body of literature that teaches IL11 is anti-inflammatory [12,[30][31][32][33]. The powerfulness of this belief led to clinical trials of rhIL11 in patients with Crohn's disease [34,35], hepatitis [36], rheumatoid arthritis [37] and psoriasis [38].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, multiple studies that used rhIL11 in mouse models showed anti-inflammatory effects and, based on this, IL11 was proposed as a therapeutic [13][14][15][16]. The absolute conviction of IL11's anti-inflammatory activity is apparent in clinical trials where rhIL11 was administered to patients with hepatitis, colitis, rheumatoid arthritis and other conditions [12].…”

Section: Introductionmentioning

confidence: 99%

“…The idea that IL11 may be anti-inflammatory remains pervasive: a thorough review of the role of IL11 in inflammatory diseases published in 2022 [12] concluded "whether this [IL11] elevation is pathogenic or a natural host response to restore homeostasis is not clear" sic. Indeed, multiple studies that used rhIL11 in mouse models showed anti-inflammatory effects and, based on this, IL11 was proposed as a therapeutic [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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IL11 stimulates IL33 expression and proinflammatory fibroblast activation

Widjaja

Chothani

Sivakumar

et al. 2022

Preprint

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Interleukin 11 (IL11) is upregulated in inflammatory conditions where it is believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 may promote inflammation, via the stroma. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in transient STAT3 phosphorylation and bi-modal ERK activation. RNA sequencing over a time course of IL11 stimulation revealed a robust short-lived transcriptional response, which was enriched for gene set hallmarks of inflammation and characterized by upregulation of SERPINB2, TNFRSF18, IL33, CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, P=9.8x10-5) and IL1RL1, its cognate receptor, was similarly increased (18-fold, P=1.1x10-34). In proteomic studies, IL11 triggered a proinflammatory secretome with notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes and lymphocytes. IL11 induced IL33 expression across fibroblast types and inhibition of STAT3, but not MEK/ERK, prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts.

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