Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation

Brasseit, Jennifer; Chung, Cheong K. C. Kwong; Noti, Mario; Zysset, Daniel; Hoheisel-Dickgreber, Nina; Genitsch, Vera; Corazza, Nadia; Mueller, Christoph

doi:10.3389/fimmu.2018.00023

Cited by 33 publications

(33 citation statements)

References 43 publications

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“…Here, mice deficient in ILC2 developed significantly ameliorated acute skin inflammation but despite the higher numbers of ILC2 present in the skin of Flg ft/ft mice, ILC2 play a redundant role in the pathogenesis of chronic dermatitis. While MC903‐induced ILC2 function could be targeted by anti‐IL‐18, we show that chronic inflammation is independent of IL‐18, further corroborating the observed redundancy of ILC2 . Although ILC2 may contribute to genesis of acute skin inflammation, their increase in numbers under chronic inflammatory conditions is probably a consequence of an overall increase in infiltrating immune cell populations.…”

Section: Discussionsupporting

confidence: 80%

Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL‐1β

Schwartz

Moran

Saunders

et al. 2019

Allergy

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BackgroundAtopic dermatitis (AD) is one of the most common skin diseases with a multifactorial etiology. Mutations leading to loss of skin barrier function are associated with the development of AD with group 2 innate lymphoid cells (ILC2) promoting acute skin inflammation. Filaggrin‐mutant (Flgft/ft) mice develop spontaneous skin inflammation accompanied by an increase in skin ILC2 numbers, IL‐1β production, and other cytokines recapitulating human AD. Here, we investigated the role of ILC2, effector cytokines, inflammasome activation, and mast cell function on the development of chronic AD‐like inflammation in mice.MethodsMice with a frameshift mutation in the filaggrin gene develop spontaneous dermatitis. Flgft/ft mice were crossed to cell‐ or cytokine‐deficient mouse strains, or bred under germ‐free conditions. Skin inflammation was scored, and microbiome composition was analyzed. Skin protein expression was measured by multiplex immunoassay. Infiltrating cells were analyzed by flow cytometry.ResultsWild‐type and Flgft/ft mice significantly differ in their microbiome composition. Furthermore, mutant mice do not develop skin inflammation under germ‐free conditions. ILC2 deficiency did not ameliorate chronic dermatitis in Flgft/ft mice, which was also independent of IL‐4, IL‐5, IL‐9, IL‐13, IL‐17A, and IL‐22. Inflammation was independent of NLRP3 inflammasome activation but required IL‐1β and IL‐1R1‐signaling. Mechanistically, IL‐1β promoted hyperactivation of IL‐1R1‐expressing mast cells. Treatment with anti‐IL‐1β‐antibody alleviated dermatitis exacerbation, while antibiotic intervention ameliorated dermatitis in neonatal mice but not in adults with established inflammation.ConclusionsIn summary, we identified a critical role for the microbiome and IL‐1β mediating chronic inflammation in mice with an impaired skin barrier.

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Section: Discussionsupporting

confidence: 80%

Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL‐1β

Schwartz

Moran

Saunders

et al. 2019

Allergy

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“…Recently, a newly identified class of innate lymphoid cells, termed ILCs, has been shown to play a pivotal role in the development of IBD and shaped by microbiome (27–30). To evaluate whether ILCs were involved in the immunological mechanism underlying the observed amelioration of the colitis in L. reuteri -treated mice, we first characterized the three canonical subsets of helper-like ILCs.…”

Section: Resultsmentioning

confidence: 99%

Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells

et al. 2019

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Immune checkpoint blockade (ICB) immunotherapy increases antitumor immunity by blocking cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and displays robust clinical responses in various cancers. However, ICB immunotherapy also triggers severe inflammatory side effects, known as immune-related adverse effects (irAEs). One of the most common toxicities is immune checkpoint blockade-associated colitis (ICB associated colitis). The exact mechanism of ICB associated colitis remains to be explored. Here, we combined ICB (anti–CTLA-4 and anti-PD-1) treatment with a standard colitis model, in which a more severe form of colitis is induced in mice, to recapitulate the clinical observations in patients receiving combined ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy, during which colitis is the most frequent complication encountered. We found that the composition of the gut microbiota changed in ICB associated colitis. Principal component analysis of the gut microbiome showed an obvious reduction in the abundance of Lactobacillus in severe ICB associated colitis. Lactobacillus depletion completely by vancomycin augmented the immunopathology of ICB. Furthermore, we found that the ICB toxicity could be totally eliminated via the administration of a widely available probiotic Lactobacillus reuteri (L.reuteri) . Oral administration of L. reuteri therapeutically inhibited the development and progression of colitis, thus ameliorating the loss of body weight and inflammatory status induced by ICB treatment. Mechanistically, the protective effect of L. reuteri was associated with a decrease in the distribution of group 3 innate lymphocytes (ILC3s) induced by ICB associated colitis. In conclusion, our study highlights the immunomodulatory mechanism of the gut microbiota and suggests that manipulating the gut microbiota by administrating L. reuteri can mitigate the autoimmunity induced by ICB, thus allowing ICB immunotherapy to stimulate the desired immune response without an apparent immunopathology.

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“…More recently, Brasseit et al have expanded on these findings by demonstrating that mice which lack ILC3 display milder colitis. Therefore, ILC appear to contribute uniquely to the innate immune response in the anti-CD40-mediated colitis model [ 115 ].…”

Section: Ilc and T Cell Complementaritymentioning

confidence: 99%

“…In turn, an in-depth study of ILC and T cells in the CD4 T cell transfer colitis model, in which the adaptive immune compartment contributes significantly, has shed a more nuanced light on the contribution of innate and adaptive immune cells to colitis development. Transfer of colitogenic CD4 T cells to Rag1 −/− mice depleted of ILC highlighted that CD4 + T cells, but not ILCs, are critical for induction of colitis [ 115 ]. Nonetheless, absence of ILC3 exacerbated histopathological signs of colitis, arguing for a non-redundant and time-specific function of ILC3 in the CD4 T cell transfer colitis model [ 115 ].…”

Section: Ilc and T Cell Complementaritymentioning

confidence: 99%

“…Transfer of colitogenic CD4 T cells to Rag1 −/− mice depleted of ILC highlighted that CD4 + T cells, but not ILCs, are critical for induction of colitis [ 115 ]. Nonetheless, absence of ILC3 exacerbated histopathological signs of colitis, arguing for a non-redundant and time-specific function of ILC3 in the CD4 T cell transfer colitis model [ 115 ].…”

Section: Ilc and T Cell Complementaritymentioning

confidence: 99%

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The roles for innate lymphoid cells in the human immune system

et al. 2018

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From constituting a novel and obscure cell population, innate lymphoid cells (ILCs) are now accepted as a self-evident part of the immune system, contributing with unique and complementary functions to immunity by production of effector cytokines and interaction with other cell types. In this review, we discuss the redundant and complementary roles of the highly plastic human ILCs and their interaction with other immune cells with the ultimate aim of placing ILCs in a wider context within the human immune system.

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Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation

Cited by 33 publications

References 43 publications

Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL‐1β

Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL‐1β

Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells

The roles for innate lymphoid cells in the human immune system

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