Abstract
Neutrophils are terminally differentiated cells with limited transcriptional activity. The biological function of their gene expression changes is poorly understood. CARD9 regulates transcription during antifungal immunity but its role in sterile inflammation is unclear. Here we show that neutrophil CARD9 mediates pro-inflammatory chemokine/cytokine but not lipid mediator release during non-infectious inflammation. Genetic deficiency of CARD9 suppresses autoantibody-induced arthritis and dermatitis in mice. Neutrophil-specific deletion of CARD9 is sufficient to induce that phenotype. Card9−/− neutrophils show defective immune complex-induced gene expression changes and pro-inflammatory chemokine/cytokine release but normal LTB4 production and other short-term responses. In vivo deletion of CARD9 reduces tissue levels of pro-inflammatory chemokines and cytokines but not LTB4. The CARD9-mediated signalling pathway involves Src-family kinases, Syk, PLCγ2, Bcl10/Malt1 and NFκB. Collectively, CARD9-mediated gene expression changes within neutrophils play important roles during non-infectious inflammation in vivo and CARD9 acts as a divergence point between chemokine/cytokine and lipid mediator release.
Highlights
Neutrophils are terminally differentiated cells with limited transcriptional activity
To test the role of CARD9 in non-infectious inflammation, we tested the effect of CARD9 deficiency on autoantibody-induced arthritis development in the K/B Â N serum-transfer model[30]
Card[9] À / À (EUCOMM) mice were strongly protected from visible signs of arthritis (Fig. 1e; P 1⁄4 6.6 Â 10–4; two-way analysis of variance (ANOVA)) and ankle thickening (Fig. 1f; P 1⁄4 0.0038; two-way ANOVA)
Summary
Neutrophils are terminally differentiated cells with limited transcriptional activity. The dissociation of neutrophil function from gene expression is best exemplified by the fact that anuclear neutrophils that have expelled their DNA through NETosis are still capable of performing various in vivo antimicrobial functions[4] Based on their short lifespan, limited transcriptional activity and robust short-term effector functions, neutrophils are generally believed to be simple effector cells of the immune and inflammatory reaction. Those non-conventional functional responses may indicate a more general role of neutrophils in the orchestration of the immune/inflammatory response[1,3,6] It is still unclear whether inflammation-related gene expression changes in neutrophils (and the resulting chemokine/cytokine production) are just evolutionary remnants from the macrophage-related origin of these cells, or they play an important functional role during the in vivo inflammation process. The role of CARD9 in neutrophils is still very poorly understood
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