IL-12 regulates type 3 immunity through interfollicular keratinocytes in psoriasiform inflammation

Zwicky, Pascale; Ingelfinger, Florian; Melo, Bruno Marcel Silva de; Ruchti, Fiorella; Schärli, Stefanie; Puertas, Nicole; Lutz, Mirjam; Phan, Truong San; Kündig, Thomas M.; Levesque, Mitchell P.; Maul, Julia‐Tatjana; Schlapbach, Christoph; LeibundGut‐Landmann, Salomé; Mundt, Sarah

doi:10.1126/sciimmunol.abg9012

Cited by 16 publications

(8 citation statements)

References 84 publications

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“…There is some evidence that IL-12 has a modulatory role in type 3 inflammation based on studies in psoriasis, and IL-13 is a potent regulator of the type 1 immune response despite its pro-inflammatory type 2 effects. 24 IL-21 is notably produced by Th17 cells, and has a role in the apoptosis of regulatory T cells in asthma. 25,26 Interestingly, IL-12 appeared to stimulate IL-21 production in an in vitro study of CD8 + T cells from Chinese CRSwNP patients, and IL-21 has anti-inflammatory effects through induction of IL-10, 20 suggesting a biological mechanism for the clustering of these cytokines in PC4.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to IL‐10, PC4 is also reduced with low levels of IL‐12, IL‐13, and IL‐21, hinting at a regulatory role for these cytokines in CRSsNP. There is some evidence that IL‐12 has a modulatory role in type 3 inflammation based on studies in psoriasis, and IL‐13 is a potent regulator of the type 1 immune response despite its pro‐inflammatory type 2 effects 24 . IL‐21 is notably produced by Th17 cells, and has a role in the apoptosis of regulatory T cells in asthma 25,26 .…”

Section: Discussionmentioning

confidence: 99%

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Association of cytokine profile with prior treatment failure and revision surgery in chronic rhinosinusitis

Longino

Labby

et al. 2022

Int Forum Allergy Rhinol

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Background Inflammatory patterns in chronic rhinosinusitis (CRS) may predict disease severity, need for multiple sinus surgeries, and treatment response. This study analyzes nasal mucus inflammatory cytokine patterns in patients with (CRSwNP) and without (CRSsNP) nasal polyposis and their association with revision sinus surgery. Methods A total of 319 CRS patients who underwent sinus surgery were included. Cytokines were quantified in intraoperative mucus specimens using a multiplex flow cytometric bead assay. Cytokine expression patterns in patients with 0, 1, and ≥2 previous surgeries were analyzed using Kruskal‐Wallis and principal component (PC) regression analyses. Results There were 122 (38%) patients with CRSsNP and 197 (62%) with CRSwNP. On univariate analysis, interleukin (IL)‐1β, IL‐6, IL‐8, and IL‐21 were associated with increasing number of sinus surgeries in CRSsNP, as were IL‐2, IL‐4, IL‐5, IL‐6, IL‐9, IL‐17A, and tumor necrosis factor (TNF)‐α in CRSwNP. PC analysis with continuous Poisson regression in CRSwNP demonstrated that high IL‐5 and IL‐13 and low IL‐1β, IL‐12, and IL‐21 were associated with more prior surgeries. In CRSsNP low IL‐13 and high IL‐5 and regulated‐on‐activation, normal T‐cell–expressed and secreted (RANTES) were associated with more prior surgeries. Age remained a significant covariate in the full regression model for CRSsNP, but was nonsignificant in CRSwNP. Conclusion In CRSwNP, elevated IL‐5 and IL‐13 levels were higher at time of surgery in patients with more prior surgeries. Type 2 cytokines in CRSsNP demonstrated mixed associations with revision surgery. For both phenotypes, IL‐10, IL‐12, and IL‐21 were consistently lower as number of prior surgeries increased, suggesting that treatment‐resistant disease may be modulated by impairment in these signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of cytokine profile with prior treatment failure and revision surgery in chronic rhinosinusitis

Longino

Labby

et al. 2022

Int Forum Allergy Rhinol

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“…We next sought to capture and localize potential sensors of IL-12, resident to the murine CNS. Leveraging the capacity of the Il12rb2 knockout-first allele to act as a reporter 12 , we used immunostaining for β-gal to detect cells expressing IL-12Rβ2 protein within the steady-state CNS, coupled with multiplexed RNA fluorescence in situ hybridization (RNAscope ® ) for Il12rb1 and Il12rb2 mRNA to capture both components of the IL-12R. IL-12R was expressed in the neuroectoderm, specifically in neurons and oligodendrocytes, already in the healthy brain (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…All mice were bred on a pure C57BL/6 background (The Jackson Laboratory, #000664) and were maintained under specific-pathogen free conditions. Knockout-first (promoter-driven) Il12rb2 fl/fl and Il12rb2 LacZ mice were generated as previously described 12 . B6.C-Tg(CMV-Cre)1Cgn/J 71 (The Jackson Laboratory, #006054) were crossed to il12rb2 fl/fl mice to generate CMV Cre/Cre Il12rb2 fl/fl or Il12rb2 del/del full knock-out (KO) mice.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective tissue adaptation induced by IL-12 attenuates CNS inflammation

Andreadou

Ingelfinger

Feo

et al. 2022

Preprint

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IL-12 is a well-established driver of type 1 immune responses. Paradoxically, in several autoimmune conditions including neuroinflammation, IL-12 reduces pathology and exhibits regulatory properties. Yet, the mechanism and the involved cellular players behind this immune regulation remain elusive. To identify the IL-12-responsive elements which prevent immunopathology, we generated mouse models lacking a functional IL-12 receptor either in all cells or in specific populations within the immune or central nervous system (CNS) compartments, and induced experimental autoimmune encephalomyelitis (EAE), which models human Multiple Sclerosis (MS). This revealed that the CNS tissue-protective features of IL-12 are mediated by cells of the neuroectoderm, and not immune cells. Importantly, sections of brain from patients with MS show comparable patterns of expression, indicating parallel mechanisms in humans. By combining spectral flow cytometry, bulk and single-nucleus RNA sequencing, we uncovered an IL-12-induced neuroprotective adaption of the neuroectoderm critically involved in maintaining CNS tissue integrity during inflammation.

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“…In turn, Th17 lymphocytes activated by IL-23 secretes effector cytokines, such as IL-17, TNF-α, IL-22, and IL-6 [ 32 ]. These cytokines lead to the inflow of neutrophils and other inflammatory cells to the skin, excessive proliferation of keratinocytes, and parakeratosis ( Figure 1 ) [ 32 , 33 , 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Abnormalities of Sphingolipids Metabolic Pathways in the Pathogenesis of Psoriasis

et al. 2023

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Psoriasis is immune-mediated skin disorder affecting thousands of people. Sphingolipids (SLs) are bioactive molecules present in the epidermis, involved in the following cellular processes: proliferation, differentiation, and apoptosis of keratinocytes. Alterations in SLs synthesis have been observed in psoriatic skin. To investigate if the imbalance in lipid skin metabolism could be related to psoriasis, we analyzed the gene expression in non-lesioned and lesioned skin of patients with psoriasis available in two datasets (GSE161683 and GSE136757) obtained from National Center for Biotechnology Information (NCBI). The differentially expressed genes (DEGs) were searched for using NCBI analysis, and Gene Ontology (GO) biological process analyses were performed using the Database of Annotation, Visualization, and Integrated Discovery (DAVID) platform. Venn diagrams were done with InteractiVenn tool and heatmaps were constructed using Morpheus software. We observed that the gene expression of cytoplasmic phospholipase A2 (PLA2G4D), glycerophosphodiester phosphodiesterase domain containing 3 (GDP3), arachidonate 12-lipoxygenase R type (ALOX12B), phospholipase B-like 1 (PLBD1), sphingomyelin phosphodiesterase 3 (SMPD3), ganglioside GM2 activator (GM2A), and serine palmitoyltransferase long chain subunit 2 (SPTLC2) was up-regulated in lesioned skin psoriasis when compared with the non-lesioned skin. These genes are related to lipid metabolism and more specifically to sphingolipids. So, in the present study, the role of sphingolipids in psoriasis pathogenesis is summarized. These genes could be used as prognostic biomarkers of psoriasis and could be targets for the treatment of patients who suffer from the disease.

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IL-12 regulates type 3 immunity through interfollicular keratinocytes in psoriasiform inflammation

Abstract: IL-12 protects from psoriasiform inflammation via interfollicular keratinocytes by promoting skin homeostasis.

Cited by 16 publications

References 84 publications

Association of cytokine profile with prior treatment failure and revision surgery in chronic rhinosinusitis

Association of cytokine profile with prior treatment failure and revision surgery in chronic rhinosinusitis

Neuroprotective tissue adaptation induced by IL-12 attenuates CNS inflammation

Abnormalities of Sphingolipids Metabolic Pathways in the Pathogenesis of Psoriasis

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