Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease

Patrick, Garrett J.; Liu, Haiyun; Alphonse, Martin P.; Dikeman, Dustin; Youn, Christine; Otterson, Jack C.; Wang, Yu; Ravipati, Advaitaa; Mazhar, Momina; Denny, George; Ortines, Roger V.; Zhang, Emily; Miller, Robert J.; Dillen, Carly; Liu, Qi; Nolan, Sabrina; Nguyen, Kristine; Marcello, Lee Ann T.; Danh, C.; Wier, Eric M.; Zhang, Yan; Caviness, Gary; Klimowicz, Alexander C.; Mierz, Diane V.; Fine, Jay S.; Sun, Guangping; Goldbach‐Mansky, Raphaela; Marusina, Alina I.; Merleev, Alexander A.; Maverakis, Emanual; Garza, Luis A.; Milner, Joshua D.; Gao, Peisong; Ramanujam, Meera; Raymond, E.; Archer, Nathan K.; Miller, Lloyd S.

doi:10.1172/jci143334

Cited by 54 publications

(52 citation statements)

References 56 publications

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“…In addition, a recent study showed that epicutaneous Staphylococcus aureus enhanced IgE production in an IL-36dependent manner. 40 Therefore, the skin barrier defect is likely to trigger an immune response in NS patients with no evidence for an immunodeficiency, as previously suggested. 14 Of note, the inflammatory properties of IL-17 and IL-36 pathways are enhanced by their capacity to mutually regulate each other.…”

Section: Discussionmentioning

confidence: 71%

Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses

Barbieux

Claustres

Fahrner

et al. 2022

Journal of Allergy and Clinical Immunology

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Section: Discussionmentioning

confidence: 71%

Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses

Barbieux

Claustres

Fahrner

et al. 2022

Journal of Allergy and Clinical Immunology

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“…Unexpectedly, IL-4 strongly increases the expression of IL36R in macrophages. In a mouse model of atopic dermatitis, IL-4 responses were required for IL-36R signaling to elevate IgE levels ( 52 ). The anti-inflammatory profile of IL-4 combined with its role in the proliferation of tissue-resident macrophages ( 53 ) may suggest an indirect role of IL-36γ in the regulation of inflammation and in the density of AT macrophages.…”

Section: Discussionmentioning

confidence: 99%

Increased Levels of Interleukin-36 in Obesity and Type 2 Diabetes Fuel Adipose Tissue Inflammation by Inducing Its Own Expression and Release by Adipocytes and Macrophages

et al. 2022

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Interleukin (IL)-36 is a recently described cytokine with well-known functions in the regulation of multiple inflammatory diseases. Since no data exists on how this cytokine regulates adipose tissue (AT) homeostasis, we aimed to explore the function of a specific isoform, IL-36γ, an agonist, in human obesity and obesity-associated type 2 diabetes as well as in AT inflammation and fibrosis. Plasma IL-36γ was measured in 91 participants in a case-control study and the effect of weight loss was evaluated in 31 patients with severe obesity undergoing bariatric surgery. Gene expression levels of IL36G and its receptor were analyzed in relevant human metabolic tissues. The effect of inflammatory factors and IL-36γ was determined in vitro in human adipocytes and macrophages. We found, for the first time, that the increased (P<0.05) circulating levels of IL-36γ in patients with obesity decreased (P<0.001) after weight and fat loss achieved by Roux-en-Y gastric bypass and that gene expression levels of IL36G were upregulated in the visceral AT (P<0.05) and in the peripheral blood mononuclear cells (P<0.01) from patients with obesity. We also demonstrated increased (P<0.05) expression levels of Il36g in the epididymal AT from diet-induced obese mice. IL36G was significantly enhanced (P<0.001) by LPS in human adipocytes and monocyte-derived macrophages, while no changes were found after the incubation with anti-inflammatory cytokines. The addition of IL-36γ for 24 h strongly induced (P<0.01) its own expression as well as key inflammatory and chemoattractant factors with no changes in genes associated with fibrosis. Furthermore, adipocyte-conditioned media obtained from patients with obesity increased (P<0.01) the release of IL-36γ and the expression (P<0.05) of cathepsin G (CTSG) in monocyte-derived macrophages. These findings provide, for the first time, evidence about the properties of IL-36γ in the regulation of AT-chronic inflammation, emerging as a link between AT biology and the obesity-associated comorbidities.

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“…Subcutaneous allergen immunotherapy has been suggested to be an effective therapeutic approach for AD (59,60), implying that allergen plays a pathogenic role in the development of AD. To better understand the role of cutaneous exposure to aeroallergens in AD, several mouse models of allergen-induced AD-like skin inflammation have been established and recognized as a powerful approach to analyze the allergen-induced pathophysiology of AD and elucidate the underlying mechanisms (43)(44)(45)(61)(62)(63). Of these, the OVA-induced AD mouse model has been well established (43)(44)(45); we therefore used OVA as a positive control to establish a new AD-like mouse model by using cockroach allergen.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell immunoreceptor drives atopic dermatitis by modulating oxidized CaMKII-involved mast cell activation

Luo¹,

Chen²,

Yang³

et al. 2022

JCI Insight

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Allergens have been identified as potential triggers in patients with atopic dermatitis (AD). Patients with AD are highly sensitive to cockroach allergen. The underlying mechanism, however, remains undetermined. Here, we established a cockroach allergen–induced AD-like mouse model, and we demonstrate that repeated exposure to cockroach allergen led to aggravated mouse skin inflammation, characterized by increased type 2 immunity, type 2 innate lymphoid cells (ILC2s), and mast cells. Increased mast cells were also observed in patients with AD. Mast cell–deficient mice ( Kit W-sh/W-sh ) showed diminished skin inflammation, suggesting that mast cells are required in allergen-induced skin inflammation. Furthermore, DC immunoreceptor (DCIR) is upregulated in skin mast cells of patients with AD and mediates allergen binding and uptake. DCIR –/– mice or reconstituted Kit W-sh/W-sh mice with DCIR –/– mast cells showed a significant reduction in AD-like inflammation. Both in vitro and in vivo analyses demonstrate that DCIR –/– mast cells had reduced IgE-mediated mast cell activation and passive cutaneous anaphylaxis. Mechanistically, DCIR regulates allergen-induced IgE-mediated mast cell ROS generation and oxidation of calmodulin kinase II (ox-CaMKII). ROS-resistant CaMKII (MM-VV δ ) prevents allergen-induced mast cell activation and inflammatory mediator release. Our study reveals a DCIR/ROS/CaMKII axis that controls allergen-induced mast cell activation and AD-like inflammation.

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Epicutaneous Staphylococcus aureus induces IL-36 to enhance IgE production and ensuing allergic disease

Cited by 54 publications

References 56 publications

Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses

Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses

Increased Levels of Interleukin-36 in Obesity and Type 2 Diabetes Fuel Adipose Tissue Inflammation by Inducing Its Own Expression and Release by Adipocytes and Macrophages

Dendritic cell immunoreceptor drives atopic dermatitis by modulating oxidized CaMKII-involved mast cell activation

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