Mouse neutrophils express the decoy type 2 interleukin-1 receptor (IL-1R2) constitutively and in acute inflammatory conditions

IL-1α and IL-1β (in this article referred to as IL-1) play important roles in host defense against infection and inflammatory diseases. IL-1R1 is the receptor for IL-1, and IL-1R2 is suggested to be a decoy receptor, because it lacks the signal-transducing TIR domain in the cytoplasmic part. However, the roles of IL-1R2 in health and disease remain largely unknown. In this study, we generated EGFP-knock-in Il1r2−/− mice and showed that they were highly susceptible to collagen-induced arthritis, an animal model for rheumatoid arthritis in which the expression of IL-1R2 is augmented in inflammatory joints. Il1r2 was highly expressed in neutrophils but had only low expression in other cells, including monocytes and macrophages. Ab production and T cell responses against type II collagen were normal in Il1r2−/− mice. Despite the high expression in neutrophils, no effects of Il1r2 deficiency were observed; however, we found that production of inflammatory mediators in response to IL-1 was greatly enhanced in Il1r2−/− macrophages. These results suggest that IL-1R2 is an important regulator of arthritis by acting specifically on macrophages as a decoy receptor for IL-1.

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

IL-1 Receptor Type 2 Suppresses Collagen-Induced Arthritis by Inhibiting IL-1 Signal on Macrophages

Shimizu

Nakajima

Sudo

et al. 2015

“…8A), leading us to investigate potential direct effects of IL-33 on myeloid cells in BMG cultures in vitro (51). Stimulation of BM cells isolated from adult WT C57BL/6 mice with rmIL-33 significantly enhanced cell proliferation during the first 2 d of culture (Fig.…”

Section: Effects Of Il-33 On Cultured Bm Cellsmentioning

confidence: 99%

“…BM-derived granulocytes (BMGs) were cultured as previously described (51). For proliferation assays, 2 3 10 5 cells/well were cultured in 96-well plates with or without G-CSF (5 ng/ml) and rmIL-33 (100 ng/ml) for indicated times before lysis in culture medium containing 1% Triton-X100 for LDH assays (Cytotoxicity Detection Kit; Roche Diagnostics, Rotkreuz, Switzerland).…”

Section: Cell Culturementioning

confidence: 99%

Severe Neutrophil-Dominated Inflammation and Enhanced Myelopoiesis in IL-33–Overexpressing CMV/IL33 Mice

Talabot-Ayer

Martin

Vesin

et al. 2015

Self Cite

IL-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous studies emphasized a role for IL-33 in shaping innate and adaptive immune responses. IL-33 was also reported to modulate myelopoiesis and myeloid cell activity. In this article, we describe IL-33–overexpressing CMV/IL33 and LysM/IL33 mice, which display an inflammatory phenotype associated with growth retardation and paw swelling. The phenotype of CMV/IL33 mice is dependent on activation of the ST2 receptor and is characterized by extensive neutrophil infiltration into different organs, including the paws. Local or systemic levels of proinflammatory mediators such as IL-1β, Cxcl-1, G-CSF, and IL-6 are increased. CMV/IL-33 mice also suffer from anemia, thrombocytosis, and a marked dysregulation of myelopoiesis, leading to an important increase in myeloid cell production or accumulation in bone marrow (BM), spleen, and peripheral blood. Consistently, recombinant IL-33 induced proliferation of myeloid lineage cells in BM-derived granulocyte cultures, whereas IL-33 knockout mice exhibited minor deficiencies in spleen and BM myeloid cell populations. Our observations reveal a neutrophil-dominated inflammatory phenotype in IL-33–overexpressing CMV/IL33 and LysM/IL33 mice, and highlight important regulatory effects of IL-33 on myelopoiesis in vitro and in vivo, where excessive IL-33 signaling can translate into the occurrence of a myeloproliferative disorder.

“…Of note, IL-1R2 binds to IL-1 with a higher affinity than to IL-1Ra, thus further enhancing the inhibitory activity of IL-1Ra (6). In contrast to the ubiquitously expressed IL-1R1, the expression of IL-1R2 is rather restricted with neutrophils being the major source in the mouse (7).…”

mentioning

confidence: 96%

Deficiency in IL-1 Receptor Type 2 Aggravates K/BxN Serum Transfer-Induced Arthritis in Mice but Has No Impact on Systemic Inflammatory Responses

Martin

Palmer

Rodriguez

et al. 2017

Self Cite

The biological activity of IL-1 is tightly regulated by the specific receptor antagonist (IL-1Ra) and the decoy receptor IL-1 receptor type 2 (IL-1R2). The role of IL-1Ra has been well demonstrated in IL-1Ra–deficient mice. In contrast, the role of endogenous IL-1R2 remains widely unknown. To define the functional role of endogenous IL-1R2 in the K/BxN serum transfer arthritis model and in IL-1β– or LPS-induced systemic inflammation in vivo, IL-1R2−/− mice were created and compared with wild type mice. IL-1R2−/− mice bred habitually and exhibited a normal phenotype. IL-1R2 deficiency aggravated arthritis severity and increased mRNA levels for key cytokines and chemokines such as IL-6, IL-1β, Cxcl-1, and Cxcl-2 significantly in ankles. There was no effect of IL-1R2 deficiency on the cell-autonomous cytokine response to IL-1β in the tested cell types, i.e., neutrophils, macrophages, and fibroblasts, but IL-1R2 deficiency on neutrophils increased the IL-1–induced response of fibroblasts in trans. Furthermore, IL-1β induced shedding of IL-1R2 in vivo. Inflammatory responses to IL-1β and LPS-induced mortality were not different in IL-1R2−/− compared with wild type mice. Our data demonstrate that the decoy receptor IL-1R2 plays an important inhibitory role in local IL-1– and neutrophil-dependent tissue inflammation as shown in the K/BxN serum transfer arthritis model. In contrast to IL-1Ra, IL-1R2 appears to be less crucial for systemic responses to acute administration of IL-1 or LPS.