The interleukin-1 receptor (IL-1R) plays an important role in mediating the inflammatory responses against pathogens. However, it is not clear whether a sustained IL-1R signaling following the loss of its endogenous inhibitor, IL-1R antagonist (IL-1RA), could improve mucosal immunity against the murine enteropathogen, Citrobacter rodentium. At basal levels, IL-1RA-deficient (IL1raKO) mice displayed an elevated inflammatory tone as indicated by their higher levels of circulating neutrophils, and the inflammatory marker, lipocalin-2, in both systemic and luminal contents. We reasoned that the heightened inflammatory tone of IL1raKO mice may be beneficial in clearing C. rodentium efficiently, but such was not the case. Oral challenge of C. rodentium (1 × 109 colony-forming units/mouse) resulted in luminal colonization, which peaked at day 7 postinfection, in both wild-type and IL1raKO mice. However, IL1raKO mice displayed a higher C. rodentium burden, and exacerbated colonic inflammation and hyperplasia. The aggravated infection in IL1raKO mice was corroborated using in vivo imaging of mice infected with a bioluminescent strain of C. rodentium. However, IL1raKO mice do not display any defect in their neutrophils with respect to their recruitment to the inflamed gut, generation of neutrophil extracellular traps and reactive oxygen species, or their ability to kill C. rodentium in vitro. In contrast, the macrophages of IL1raKO mice were able to upregulate more inducible nitric oxide synthase and produce more nitrite that wild-type macrophages; however, the former was less effective in mediating killing of C. rodentium in vitro. Together, our results suggest that IL-1RA plays a protective role in combating enteropathogen infection.

Autoinflammatory bone diseases (AIBDs) constitute a recently identified subset of autoinflammatory diseases. These conditions are characterized by an exaggerated inflammatory response in the bones without any apparent etiology. Inflammatory bone lesions associated with AIBDs exhibit chronic inflammation, are typically culture-negative, and do not exhibit discernible microorganisms on histopathological examination. The most common and representative AIBD is chronic non-bacterial osteomyelitis (CNO), which is also known as chronic recurrent multifocal osteomyelitis. Another variant of CNO, which is typically observed in older teenagers or adults, is known as synovitis, acne, hyperostosis, pustulosis, osteitis syndrome. This condition is distinguished by its notable skin manifestations. Advancements in genetic research have led to the identification of three novel monogenic subtypes within the category of AIBDs. These include Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome, and interleukin-1 receptor antagonist deficiency syndrome. Another monogenic AIBD, called cherubism, affects only the maxilla and mandible. Data on the diagnosis and treatment of these rare diseases are extremely limited. However, if not diagnosed and treated promptly, it can result in significant complications, including severe disability and mortality. Thus, it is imperative to maintain a high level of clinical awareness of these diseases. These rare diagnoses should be considered in patients with musculoskeletal complaints in whom no specific etiology can be identified or in patients with systemic manifestations such as cutaneous and gastrointestinal symptoms or fever. In such patients, the diagnostic process, which encompasses imaging and genetic studies, should be initiated promptly.

The study aimed to conduct a systematic literature review of the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of patients with deficiency of the interleukin-1 receptor antagonist (DIRA) and determine the practical contributions that the current scientific literature offers concerning the clinical and epidemiological aspects of DIRA. A systematic review of the literature was conducted in the PubMed, Scopus, Web of Science, and the Virtual Health Library databases between January 2009 and June 2024 in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol. The following MeSH descriptors were used: "interleukin-1 receptor antagonist deficiency," "epidemiology," "clinical manifestations," "treatment," and "physiopathology." Of the 3,749 articles, 18 met the eligibility criteria. The findings were divided by heuristic questions into three groups: "epidemiological and genetic aspects of patients with DIRA," "clinical and laboratory characterization in DIRA," and "therapeutic approach to patients with DIRA." DIRA appears to be more common in males around four years of age. Several IL-1RN mutations were described, varying according to the geographic location. The most common symptoms were fever, followed by osteoarticular manifestations (arthralgia, muscle contracture, fracture, osteolytic lesions, and osteomyelitis), nail changes, pneumonia, venous thrombosis, and, in severe cases, multiple organ failure. There were no specific laboratory markers. Canakinumab was the drug of choice; however, glucocorticoids, rilonacept, and anakinra have been used.

When IL-1 receptor antagonist (IL-1rn) is knocked out, mice have shown strain background dependent and major QTL regulated susceptibility to spontaneously inflammatory arthritis disease (SAD). The impact on bone properties resulting from the interactions of IL-1rn, genomic background strains, and the QTL locus, is unknown. Bone properties in the four specifically bred mouse strains with mutation of IL-1rn and variations in genomic components were investigated with high-resolution MicroCT and genomic analytical tools. Two congenic mouse strains were also measured to evaluate the influence on bone properties by a QTL in the region in chromosome 1. Our results reveal that several bone phenotypes, including bone mineral density (BMD), bone volume, tibial length, and cortical thickness of the tibia are different between wild type and IL-1rn knockout mice in both Balb/c and DBA/1 backgrounds, but IL-1rn knockout affects BMD differently between the two mouse strains. The absence of IL-1rn decreases BMD in Balb/c mice but increases BMD in DBA/1-/- mice compared to their respective wild type counterparts. A QTL transferred from the Balb/c genetic background which affects arthritis in congenic strains appears to also regulate BMD. While several genes, including Ctsg and Prg2, may affect BMD, Ifi202b is the most favored candidate gene for regulating BMD as well as SAD. In conclusion, the previously mentioned bone phenotypes are each influenced in different ways by the loss of IL-1ra when considered in mice from varying genomic backgrounds.

Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have a genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from a non-consanguineous healthy couple, with a neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations and a fatal outcome in infancy. We conducted DNA and mRNA analyses in the patients' healthy relatives to identify the genetic cause of the patients' disease. DNA analyses were performed by both Sanger and next-generation sequencing, which identified two novel heterozygous IL1RN variants: the intronic c.318 + 2T>G variant in the father and a ≈2,600-bp intragenic deletion in the mother. IL1RN mRNA production was markedly decreased in both progenitors when compared with healthy subjects. The mRNA sequencing performed in each parent identified two novel, truncated IL1RN transcripts. Additional experiments revealed a perfect intrafamilial phenotype-genotype segregation following an autosomal recessive inheritance pattern. The evidences shown here supported for the presence of two novel loss-of-function (LoF) IL1RN pathogenic variants in the analyzed family. Biallelic LoF variants at the IL1RN gene cause the deficiency of interleukin-1 receptor antagonist (DIRA), a monogenic autoinflammatory disease with marked similarities with the patients described here. Despite the non-availability of the patients' samples representing the main limitation of this study, the collected evidences strongly suggest that the patients described here suffered from a lethal form of DIRA likely due to a compound heterozygous genotype at IL1RN, thus providing a reliable genetic diagnosis based on the integration of old medical information with currently obtained genetic data.