High-density lipoproteins inhibit urate crystal-induced inflammation in mice

Abstract

Objectives To investigate the effects and mechanisms of action of high-density lipoproteins (HDL) in monosodium urate (MSU) crystal-induced inflammation -that is, gouty inflammation, in vivo. Methods Air pouches raised on the backs of mice were injected with MSU crystals or tumour necrosis factor (TNF) in the presence or absence of HDL and/or interleukin (IL)-1 receptor antagonist (IL-1Ra) for 3 h. Leucocyte count and neutrophil percentage in pouch fluids were measured using a haemocytometer and May-Grünwald-Giemsa staining. The cytokine production and expression in the pouch were measured by ELISA and quantitative RT-PCR. Results MSU crystals induced leucocyte infiltration, mostly neutrophils, and the release of IL-1β, IL-6, chemokine (C-X-C motif ) ligand 1 (CXCL1), chemokine (C-C motif ) ligand 2 (CCL2) and IL-1Ra in pouch fluids. TNF remained under the detection limit. MSU crystals triggered IL-1β, IL-6 and CXCL1 expression in both pouch exudates and membranes, whereas CCL2 and TNF mRNA were not modulated. The co-injection of MSU crystals and HDL inhibited leucocyte influx by 59% and neutrophil infiltration by 83% and, in turn, both protein and mRNA levels of all assessed proinflammatory cytokines were reduced, but not those of IL-1Ra. Similar results were obtained when mice were injected with MSU crystals pretreated with HDL or TNF instead of crystals. When HDL and IL-1Ra were added together they displayed additional inhibition, suggesting different mechanisms of action. Conclusions This study demonstrated that HDL may represent an important factor in the modulation of gouty inflammation by acting on both tissue and infiltrating cells -that is, synovial tissue and synovial fluid cells. HDL display anti-inflammatory activity, in part, by interacting with crystals but also by directly acting on cells.

High‐density lipoprotein reduces inflammation from cholesterol crystals by inhibiting inflammasome activation

“…Whereas further studies are needed to better understand the exact molecular mechanism and integral components of HDL that are required, we have described a new pathway through which HDL could suppress inflammation caused by CC in atherosclerotic plaque. Results from this study may also help to explain the beneficial effects of HDL that have been described in other crystalline diseases, such as gout and silicosis …”

How Factors Involved in the Resolution of Crystal-Induced Inflammation Target IL-1β

“…Interestingly, HDL do not affect the production of the crystal-induced anti-inflammatory factor IL-1Ra. Unlike other lipoproteins, HDL may act not only by adhering to the surface of the crystals, but also through a direct interaction with the inflammatory cells (Scanu et al, 2015). …”

“…Anti-inflammatory cytokine assessment in SF demonstrated that IL-1Ra levels are higher in gouty patients than in osteoarthritis patients (Chen et al, 2011). The injection of MSU crystals into a murine air pouch causes IL-1Ra production after 3 h, although the levels detected are not sufficient to inhibit the inflammatory effect of IL-1β at that same time point (Scanu et al, 2015). In vitro stimulation of monocytes/macrophages by synthetic MSU, CPP and basic calcium phosphate (BCP) crystals induces a rapid increase in pro-inflammatory cytokines such as IL-1β, IL-8 and IL-6, whereas longer periods are required to release high levels of IL-1Ra (a personal observation).…”

Could MicroRNAs be Regulators of Gout Pathogenesis?

“…Some CXC chemokines, of which interleukin-8 (CXCL8) is the classic type, attract polymorphonuclear leukocytes to sites of acute inflammation. There are a number of chemokines and their receptors identified to have some roles in acute gouty arthritis, such as CCL2, CCL3, CCL4, CXCL1,CXCL2, CXCL8(IL-8), CXCL10, CXCL16, CCR5, CXCR2, CXCR4, and CXCR6 [54][55][56][57].…”