The anti-inflammatory, artificially programmed M3 macrophage phenotype restricts crystal-induced gouty inflammation in vitro

Abstract

Gout is a common cause of inflammatory arthritis, joint damage, kidney stones, and kidney failure. Joint inflammation is induced by interaction of uric acid (monosodium urate, MSU) crystals and calcium pyrophosphate (CaPP) crystals with macrophages. We hypothesized that the crystal-induced inflammation could be suppressed by the M3 switch phenotype, which increases production of anti-inflammatory cytokines under the action of inflammation inducers (AB-M3 phenotype).
The aim of the present study was to test this hypothesis.
Methods. Gouty inflammation was modeled by adding MSU and CaPP crystals to cultured macrophages. The inflammasome inhibitor, MCC950, and IL-4 were used for programming the AB-M3 phenotype. The inflammatory response was evaluated by production of IL-1β and TGFβ1.

Results. The response of native (M0) macrophages to either MSU crystals or CaPP crystals reproduced acute gouty inflammation in the form of a 3-fold increase in IL-1 β production (p < 0.05). When MSU crystals were added to AB-M3 macrophages, the IL-1β content in the culture medium became 25 times lower (p < 0.05), and the TGF-β1 content became almost twice higher (p < 0.05) than the respective values in the M0 macrophage medium with MSU crystals. A similar result was obtained when CaPP crystals were added to AB-M3 macrophages.
Conclusion. The AB-M3 phenotype responds to the pro-inflammatory action of MSU and CaPP crystals by decreasing the IL-1β production and increasing the TGF-β1 production. These results confirmed the hypothesis that the AB-M3 phenotype restricts the crystal-induced production of inflammatory IL-1β and increases the production of anti-inflammatory TGF-β1. Therefore, development of a clinical version of the AB-M3 macrophage technology is very promising.