Elastic-Vessel Arteritis in Interleukin-1 Receptor Antagonist–Deficient Mice Involves Effector Th1 Cells and Requires Interleukin-1 Receptor

Abstract

Background-In mice that lack interleukin-1 receptor antagonist (IL-1ra), transmural inflammation of the elastic arteries develops at sites of turbulent flow. We described late histopathology previously. Here, we investigate the cellular events in nonlethal arteritis at the aortic root and compare them with Takayasu's arteritis and giant cell arteritis. Methods and Results-IL-1ra-deficient mice were inbred from the original stocks and from BALB/c backcrosses. Disease was ascertained histologically and immunohistologically postmortem at the aortic root. Onset appeared to be stochastic and was not detectably age dependent; in our local Sf3 strain, the half-time of onset was Ϸ52 days. Loss of the type I IL-1 receptor suppressed the arteritis. Microvascular activation, as determined by absence of strong E-selectin expression, was absent from preaffected vessels. In mildly affected cases, infiltration was adventitial. In severely affected animals, infiltrates appeared to be active in destroying elastin, but resynthesis of disorganized elastin occurred at closely adjacent sites. Infiltrates consisted predominantly of macrophages but were rich in CD4 ϩ -interferon-␥ ϩ cells, which are likely to represent Th1 cells. Dendritic cells accumulated in lesional areas. Conclusions-The

Pro-Inflammatory Interleukin-1 Genotypes Potentiate the Risk of Coronary Artery Disease and Cardiovascular Events Mediated by Oxidized Phospholipids and Lipoprotein(a)

“…Transgenic mouse models with variations in IL-1 genotypes further support the causal role of IL-1 in atherogenesis(reviewed in (3,26)). In IL-1 receptor antagonist knockout mice, unopposed IL-1 biological activity resulted in spontaneous arterial inflammation with massive infiltration of macrophages and CD4+, interferon γ+ T-cells at branch points in mid and large arteries(52,53). Decreases in IL-1 biological activity in apoE-deficient mice decreased the rate and extent of atherosclerosis formation(54,55).…”

Expression of Th2-skewed pathology mediators in monocyte-derived type 2 of dendritic cells (DC2)

“…macrophage inflammatory protein-1 (MIP-1␣), is ligand for CCR1 and CCR5 chemokine receptors that are also thought to be therapeutic targets for asthma [49]. Although detailed correlation between IL-1 and IL1RN productions remains to be elucidated in diseases, expression of this gene is suggested to contribute to suppression of Th1-skewed immunobalance [50][51][52]. STAB1, which is induced in Th2-polarized alternatively activated macrophage and is a cellular receptor for SPARC, may be involved in intracellular protein transport upregulated in Th2-skewed immune responses [53].…”

Impact of IL-1 signalling on experimental uveitis and arthritis

“…Female IL1R KO and IL1RN KO (IL-1Ra KO) mice on the BALB/c background have been described 18 22. All animal experiments complied with the ethics and animal experiment regulations of the Association of Assessment and Accreditation of Laboratory Animal Care International and our Institutional Animal Care and Use Committee.…”