Thymic stromal lymphopoietin deficiency attenuates experimental autoimmune encephalomyelitis

Eckhardt, Jenny; Döbbeler, M.; König, Christina; Kuczera, Katarzyna; Kuhnt, Christine; Ostalecki, Christian; Zinser, Elisabeth; Mak, T. W.; Steinkasserer, Alexander; Lechmann, Matthias

doi:10.1111/cei.12621

Cited by 12 publications

(9 citation statements)

References 51 publications

(87 reference statements)

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“…Our data suggest that TSLP-producing cells are a more general means by which immune responses are facilitated, as they suppress the Treg cell response. In addition, these changes in the number of Treg cells in the blood after deletion of Tslpr correlate with alleviation of neuroinflammation and restoration of myelin expression, which is in agreement with a previous study showing that EAE symptoms are ameliorated in Tslp −/− mice [ 49 ]. In fact, the epithelial cell-derived cytokines TSLP, GM-CSF, and IL-25 have been shown to be master initiators of type 3 inflammation via their effects on a variety of cells, including Th17 cells, ILC3, and mast cells [ 50–52 ].…”

Section: Discussionsupporting

confidence: 92%

The autoimmune encephalitis-related cytokine TSLP in the brain primes neuroinflammation by activating the JAK2-NLRP3 axis

et al. 2021

Clinical and Experimental Immunology

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NLRP3 inflammasome hyperactivation contributes to neuroinflammation in autoimmune disorders, but the underlying regulatory mechanism remains to be elucidated. We demonstrate that compared with wild-type (WT) mice, mice lacking thymic stromal lymphopoietin (TSLP) receptor (TSLPR) (Tslpr -/- mice) exhibit a significantly decreased experimental autoimmune encephalitis (EAE) score, reduced CD4 + T cell infiltration, and restored myelin basic protein (MBP) expression in the brain after EAE induction by myelin oligodendrocyte glycoprotein35-55 (MOG35-55). TSLPR signals through Janus kinase (JAK)2, but not JAK1 or JAK3, to induce NLRP3 expression, and Tslpr -/- mice with EAE show decreased JAK2 phosphorylation and NLRP3 expression in the brain. JAK2 inhibition by ruxolitinib mimicked loss of TSLPR function in vivo and further decreased TSLP expression in the EAE mouse brain. The NLRP3 inhibitor MCC950 decreased CD4 + T cell infiltration, restored MBP expression, and decreased IL-1β and TSLP levels, verifying the proinflammatory role of NLRP3. In vitro experiments using BV-2murine microglia revealed that TSLP directly induced NLRP3 expression, phosphorylation of JAK2 but not JAK1orJAK3, and IL-1β release, which were markedly inhibited by ruxolitinib. Furthermore, EAE induction led to an increase in the Th17 cell number, a decrease in the regulatory T (Treg) cell number in the blood, and an increase in the expression of the cytokine IL-17A in the WT mouse brain, which was drastically reversed in Tslpr -/- mice. In addition, ruxolitinib suppressed the increase in IL-17A expression in the EAE mouse brain. These findings identify TSLP as a prospective target for treating JAK2-NLRP3 axis-associated autoimmune inflammatory disorders.

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Section: Discussionsupporting

confidence: 92%

The autoimmune encephalitis-related cytokine TSLP in the brain primes neuroinflammation by activating the JAK2-NLRP3 axis

et al. 2021

Clinical and Experimental Immunology

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“…TSLPR-deficient mice showed less severe arthritis in collagen-induced autoimmune arthritis ( 149 ). In a model of experimental autoimmune encephalomyelitis (EAE), TSLP-knock-out mice displayed a delayed outset of disease and an attenuated form of EAE ( 150 ). These studies suggest that TSLP–TSLPR axis might contribute to the pathogenesis of autoimmune disorders.…”

Section: Tslp and Autoimmune Disordersmentioning

confidence: 99%

Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer

et al. 2018

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Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.

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“…For the visualization of inflammatory infiltrates, spinal cords from perfused EAE mice were harvested on day 17, fixed in liquid nitrogen and stored at −80°C. Preparation of spinal cord sections and Luxol fast blue-staining to indicate demyelinated areas was performed according to protocols as described previously (28).…”

Section: Methodsmentioning

confidence: 99%

Endogenous Expression of the Human CD83 Attenuates EAE Symptoms in Humanized Transgenic Mice and Increases the Activity of Regulatory T Cells

et al. 2019

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The CD83 is a type I membrane protein and part of the immunoglobulin superfamily of receptors. CD83 is involved in the regulation of antigen presentation and dendritic cell dependent allogeneic T cell proliferation. A soluble form of CD83 inhibits dendritic cell maturation and function. Furthermore, CD83 is expressed on activated B cells, T cells, and in particular on regulatory T cells. Previous studies on murine CD83 demonstrated this molecule to be involved in several immune-regulatory processes, comprising that CD83 plays a key role in the development und function of different immune cells. In order to get further insights into the function of the human CD83 and to provide preclinical tools to guide the function of CD83/sCD83 for therapeutic purposes we generated Bacterial Artificial Chromosomes (BAC) transgenic mice. BACs are excellent tools for manipulating large DNA fragments and are utilized to engineer transgenic mice by pronuclear injection. Two different founders of BAC transgenic mice expressing human CD83 (BAC-hCD83 tg mice) were generated and were examined for the hCD83 expression on different immune cells as well as both the in vitro and in vivo role of human CD83 (hCD83) in health and disease. Here, we found the hCD83 molecule to be present on activated DCs, B cells and subtypes of CD4 + T cells. CD8 + T cells, on the other hand, showed almost no hCD83 expression. To address the function of hCD83, we performed in vitro mixed lymphocyte reactions (MLR) as well as suppression assays and we used the in vivo model of experimental autoimmune encephalomyelitis (EAE) comparing wild-type and hCD83-BAC mice. Results herein showed a clearly diminished capacity of hCD83-BAC-derived T cells to proliferate accompanied by an enhanced activation and suppressive activity of hCD83-BAC-derived Tregs. Furthermore, hCD83-BAC mice were found to recover faster from EAE-associated symptoms than wild-type mice, encouraging the relevance also of the hCD83 as a key molecule for the regulatory phenotype of Tregs in vitro and in vivo .

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Thymic stromal lymphopoietin deficiency attenuates experimental autoimmune encephalomyelitis

Cited by 12 publications

References 51 publications

The autoimmune encephalitis-related cytokine TSLP in the brain primes neuroinflammation by activating the JAK2-NLRP3 axis

The autoimmune encephalitis-related cytokine TSLP in the brain primes neuroinflammation by activating the JAK2-NLRP3 axis

Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer

Endogenous Expression of the Human CD83 Attenuates EAE Symptoms in Humanized Transgenic Mice and Increases the Activity of Regulatory T Cells

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