Myeloid Src-family kinases are critical for neutrophil-mediated autoinflammation in gout and motheaten models

Abstract

Autoinflammatory diseases include a number of monogenic systemic inflammatory diseases, as well as acquired autoinflammatory diseases such as gout. Here, we show that the myeloid Src-family kinases Hck, Fgr, and Lyn are critical for experimental models of gout, as well as for genetically determined systemic inflammation in the Ptpn6me-v/me-v (motheaten viable) mouse model. The Hck−/−Fgr−/−Lyn−/− mutation abrogated various monosodium urate (MSU) crystal–induced pro-inflammatory responses of neutrophils, and protected mice from the development of gouty arthritis. The Src-family inhibitor dasatinib abrogated MSU crystal–induced responses of human neutrophils and reduced experimental gouty arthritis in mice. The Hck−/−Fgr−/−Lyn−/− mutation also abrogated spontaneous inflammation and prolonged the survival of the Ptpn6me-v/me-v mice. Spontaneous adhesion and superoxide release of Ptpn6me-v/me-v neutrophils were also abolished by the Hck−/−Fgr−/−Lyn−/− mutation. Excessive activation of tyrosine phosphorylation pathways in myeloid cells may characterize a subset of autoinflammatory diseases.

Spatiotemporal Observation of Monosodium Urate Crystals Deposition in Synovial Organoids Using Label-Free Stimulated Raman Scattering

“…This process enabled us to achieve hyperspectral SRS capability with matched group velocity dispersion. We acquired spectral information by scanning the time delay between the pump and stokes pulses using a delay line [ 32 , 33 ]. The pump and stokes beams were then combined and introduced into a laser-scanning microscope (FV1200, Olympus).…”

“…We utilized the open-source software ImageJ [ 33 ] to delineate the lining and sublining areas within the synovium organoid. Initially, the background of each image for the 3 chemicals was removed by subtracting the corresponding off-resonant images.…”