Contribution of Mast Cell–Derived Interleukin‐1β to Uric Acid Crystal–Induced Acute Arthritis in Mice

Abstract

Objective Gouty arthritis is caused by precipitation in joints of crystals of monosodium urate (MSU). While it has been reported that mast cells (MCs) infiltrate gouty tophi, little is known about the actual roles of MCs during acute attacks of gout. This study was undertaken to assess the role of MCs in a mouse model of MSU crystal-induced acute arthritis. Methods We assessed the effects of intra-articular (i.a) injection of MSU crystals in various strains of mice with constitutive or inducible MC deficiency, or in mice lacking IL-1β or other elements of innate immunity. We also assessed response to i.a. injection of MSU crystals in genetically MC-deficient mice after i.a. engraftment of wild-type or IL-1β−/− bone marrow-derived cultured MCs. Results We show that MCs can augment acute tissue swelling following i.a. injection of MSU crystals in mice. We report further that IL-1β production by MCs contributes importantly to MSU crystal-induced tissue swelling, particularly during its early stages, and that selective depletion of synovial MCs can diminish MSU crystal-induced acute inflammation in the joints. Conclusion Our findings identify a previously unrecognized role for MCs and MC–derived IL-1β in contributing to the early stages of MSU crystal-induced acute arthritis in mice.

CARD8 rs2043211 Polymorphism is Associated with Gout in a Chinese Male Population

“…Recent studies have suggested that MSU crystals might function as a danger signal released from injured cells and trigger an innate immune response in a manner similar to microbial molecules, implying gouty arthritis as a paradigm of innate immunity [20,21]. The NALP3 inflammasome, including CARD8 can control inflammatory caspase-1-mediated IL-1 release and is involved in MSU crystals-mediated gouty arthritis [22,23].…”

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

“…), intra-articularly (i.a.) (Reber, Marichal, et al, 2014), or intra-cranially (Arac et al, 2014; Christy, Walker, Hessner, & Brown, 2013) to create so-called MC knockin mice. Since their description in 1985 (Nakano et al, 1985), such MC knockin mice have been widely employed to assess the importance of MCs in regulating the expression of biological responses in vivo .…”

“…One promising approach for achieving the selective and efficient depletion of a particular cell population is the injection of diphtheria toxin (DT) into transgenic mice bearing the DT receptor (DTR) only in that particular cell type (Buch et al, 2005). This approach was recently used by three different groups to deplete MCs in adult mice (Dudeck et al, 2011; Otsuka et al, 2011; Reber, Marichal, et al, 2014; Sawaguchi et al, 2012) (Table 1). Another group generated a mouse strain in which a tamoxifen-inducible Cre is expressed under the control of the endogenous c- kit locus (Heger, Seidler, et al, 2014).…”

“…We mated Cpa3-Cre mice with iDTR fl/fl mice, to achieve Cre-dependent expression of DTR in MCs and basophils (Reber, Marichal, et al, 2014). We found that a single i.p.…”

Analyzing the Functions of Mast Cells <em>In Vivo</em> Using '<em>Mast Cell Knock-in</em>' Mice

“…If we obtain concordant results in both types of MC-deficient mice, we then proceed to engraftment experiments to ascertain the role of MCs and assess the potential roles of certain MC-derived products. Finally, it should be noted that several strains allowing inducible depletion of MCs or Cre recombinase-mediated deletion of "floxed" genes in MCs have also been recently described 25,49,61 . These strains have been reviewed in detail elsewhere 9,10,13 and represent promising alternative -or complementary -approaches to study MC functions in vivo.…”