Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis.

BACKGROUND: Perturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. Mice deficient in interleukin-1 receptor antagonist (Il1rn -/- mice) spontaneously develop autoimmune arthritis and are susceptible to other autoimmune diseases such as psoriasis, diabetes, and encephalomyelitis; however, the mechanisms of increased susceptibility to these autoimmune phenotypes are poorly understood. We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of commensal intestinal microbiota, and assessed the involvement of microbiota subsets and innate and adaptive mucosal immune responses that underlie the development of spontaneous arthritis in Il1rn -/- mice. RESULTS: Using high-throughput 16S rRNA gene sequencing, we show that IL-1Ra critically maintains the diversity and regulates the composition of intestinal microbiota in mice. IL-1Ra deficiency reduced the intestinal microbial diversity and richness, and caused specific taxonomic alterations characterized by overrepresented Helicobacter and underrepresented Ruminococcus and Prevotella. Notably, the aberrant intestinal microbiota in IL1rn -/- mice specifically potentiated IL-17 production by intestinal lamina propria (LP) lymphocytes and skewed the LP T cell balance in favor of T helper 17 (Th17) cells, an effect transferable to WT mice by fecal microbiota. Importantly, LP Th17 cell expansion and the development of spontaneous autoimmune arthritis in IL1rn -/- mice were attenuated under germ-free condition. Selective antibiotic treatment revealed that tobramycin-induced alterations of commensal intestinal microbiota, i.e., reduced Helicobacter, Flexispira, Clostridium, and Dehalobacterium, suppressed arthritis in IL1rn -/- mice. The arthritis phenotype in IL1rn -/- mice was previously shown to depend on Toll-like receptor 4 (TLR4). Using the ablation of both IL-1Ra and TLR4, we here show that the aberrations in the IL1rn -/- microbiota are partly TLR4-dependent. We further identify a role for TLR4 activation in the intestinal lamina propria production of IL-17 and cytokines involved in Th17 differentiation preceding the onset of arthritis. CONCLUSIONS: These findings identify a critical role for IL1Ra in maintaining the natural diversity and composition of intestinal microbiota, and suggest a role for TLR4 in mucosal Th17 cell induction associated with the development of autoimmune disease in mice.

Gossypium herbaceam L. extracts ameliorate disequilibrium of IL-1RA/IL-1ß ratio to attenuate inflammatory process induced by amyloid ß in rats.

A chronic inflammatory response possibly mediated by Amyloid ß (Aß) is believed to be a major factor in the pathology of Alzheimer's disease (AD). Studies suggest that the mediators of the inflammatory response, which might contribute to brain damage, involve cytokines, such as IL-1ß. IL-1ß could play an important part in the development of pathologic conditions. There is also an endogenous interleukin-1 receptor antagonist (IL-1RA) in IL-1 family, which could prevent the actions of IL-1ß by competing for receptor binding without inducing any signal transduction. Therefore, the balance of IL-1ß vs IL-1RA is a critical parameter in determining not only whether excessive host inflammation will occur, but also the degree of subsequent host cell damage and associated toxicity. In our previous study, it has been determined that the anti-inflammatory action of Gossypium herbaceam L. extracts (GHE) was involved in its neuroprotection. However, the effects of GHE on IL-1ß and IL-1RA have not been clearly defined in the experimental rat model of AD induced by Aß. Therefore, the current study is performed to evaluate whether GHE could affect the disequilibrium of IL-1RA/IL-1ß ratio in the hippocampus of rats after Aß treatment. Subsequently, we further identify that GHE could efficaciously promote Akt and GSK3ß phosphorylation, and thereby contribute to IL-1ß release decrease as well as a concurrent increase in the level of IL-1RA through NF-κB and MAPK pathways. As a consequence, GHE is potentially beneficial to maintain the endogenous IL-1RA/ IL-1ß balance in the hippocampus of rats and it might be a potential agent to ameliorate inflammatory process in AD.

Systematic review and stratified meta-analysis of the efficacy of interleukin-1 receptor antagonist in animal models of stroke.

BACKGROUND: Interleukin (IL)-1 receptor antagonist (RA) is an anti-inflammatory protein used to treat arthritis that has also been identified as a candidate stroke drug. METHODS: We conducted a systematic review and meta-analysis of reports of the efficacy of IL-1 RA in animal models of focal cerebral ischemia. RESULTS: We identified 16 published sources and one unpublished source of data. IL-1 RA reduced infarct volume by 38.2% (95% confidence interval 31.2%-45.1%). Efficacy was higher with higher doses, earlier treatment, and central administration of drug. No studies used animals with hypertension or diabetes or tested efficacy beyond 3 hours. CONCLUSIONS: The animal data supporting IL-1 RA as a candidate drug for stroke are limited, and further experiments are required before proceeding to clinical trial.

Active immunization with IL-1 displayed on virus-like particles protects from autoimmune arthritis.

IL-1 is an important mediator of inflammation and a major cause of tissue damage in rheumatoid arthritis (RA). Therapeutic administration of recombinant IL-1 receptor antagonist (IL-1Ra) is efficacious in reducing clinical symptoms of disease, but suffers from several drawbacks, including the need for frequent administrations of large amounts. Here, we show that immunization of mice with either IL-1alpha or IL-1beta chemically cross-linked to virus-like particles (VLP) of the bacteriophage Qbeta elicited a rapid and long-lasting autoantibody response. The induced Ab efficiently neutralized the binding of the respective IL-1 molecules to their receptors in vitro and their pro-inflammatory activities in vivo. In the collagen-induced arthritis model, both vaccines strongly protected mice from inflammation and degradation of bone and cartilage. Moreover, immunization with either vaccine showed superior efficacy than daily administrations of high amounts of IL-1Ra. In the T and B cell-independent collagen Ab transfer model, immunization with the IL-1beta vaccine strongly protected from arthritis, whereas immunization with the IL-1alpha vaccine had no effect. Our results suggest that active immunization with IL-1alpha, and especially IL-1beta conjugated to Qbeta VLP, might become an efficacious and cost-effective new treatment option for RA and other systemic IL-1-dependent inflammatory disorders.

Developing a service for biologic therapies: a personal experience.

Tumour necrosis factor alpha (TNFalpha) has been identified in the pathogenesis of synovitis and joint destruction in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Therefore selected targeting of pathogenic elements of disease is possible (Chu et al., 1991). TNFalpha is a pro-inflammatory cytokine (mediator) and the over-expression of mediators is considered to be responsible for the damage to articular cartilage in bones. Elevated levels of TNFalpha, correlating with disease activity, have been measured in the serum and synovial fluid of patients with rheumatic diseases and are therefore an ideal target for therapy (Mangge et al., 1995; Cope et al., 1992). The National Institute for Clinical Excellence (NICE) approved the use of two therapies; entanercept (Enbrel) and infliximab (Remicade) for use in patients with active RA in 2002 (NICE, 2002). Other biologic treatments including adalimumab (D2E7) and anakinra (Kineret) will also be available for use in the future. This paper explores the development of a service to provide these therapies to patients.