Dataset Information

Regulatory Role of IL-1R8 in Immunity and Disease.

ABSTRACT: Interleukin-1 receptor family members (ILRs) and toll-like receptors (TLRs) are characterized by the presence of a conserved intracellular domain and the toll-IL-1resistance (TIR) domain and are key players in immunity and inflammation. ILR and TLR signaling is tightly regulated at different levels. All cell types of the innate immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R8, also known as TIR8 or SIGIRR, is a fringe member of the ILR family and acts as a negative regulator of ILR and TLR signaling, which dampens ILR- and TLR-mediated cell activation. IL-1R8 is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R8, focusing on its role in different pathological conditions, ranging from infectious and sterile inflammation to autoimmunity and cancer-related inflammation.

SUBMITTER: Molgora M

PROVIDER: S-EPMC4837151 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Regulatory Role of IL-1R8 in Immunity and Disease.

Molgora Martina M Barajon Isabella I Mantovani Alberto A Garlanda Cecilia C

Frontiers in immunology 20160420

Interleukin-1 receptor family members (ILRs) and toll-like receptors (TLRs) are characterized by the presence of a conserved intracellular domain and the toll-IL-1resistance (TIR) domain and are key players in immunity and inflammation. ILR and TLR signaling is tightly regulated at different levels. All cell types of the innate immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cell ...[more]

PMID: 27148268

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Project description:Background: Interleukin 37 (IL-37), a member of IL-1 family, broadly suppresses inflammation in many pathological conditions by acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex IL1-R5/IL-1R8, but it can also translocate to the nucleus. However, whether IL-37 exerts beneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to be elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8. Methods: We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and double transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recombinant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in blood peripheral mononuclear cells and brain tissue samples of MS patients. Results: We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice by acting via IL1-R5/IL1-R8. We also reveal that administration of recombinant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral blood mononuclear cells and in brain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed. Conclusions: This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE by acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.

Dataset Information

Regulatory Role of IL-1R8 in Immunity and Disease.

Publications

Regulatory Role of IL-1R8 in Immunity and Disease.

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