Macrophage differentiation of myeloid progenitor cells in response to M-CSF is regulated by the dual-specificity phosphatase DUSP5

Abstract

M-CSF regulates the production, survival, and function of monocytes and macrophages. The MAPKs ERK1/2 are key elements for signal integration downstream of the M-CSFR, and their sustained activation is essential for macrophage differentiation. In this study, we sought to isolate genes whose induction by M-CSF is dependent on persistent MAPK activation, thereby being possibly involved in the commitment of myeloid progenitors to macrophage differentiation. Following SSH between cDNA libraries from FD-Fms cells stimulated by M-CSF for 8 h in the presence or the absence of the MEK inhibitor U0126, we isolated DUSP5. DUSP5 expression is induced by M-CSF in various myeloid cells and acts as a specific negative-feedback regulator of ERK1/2. In FD-Fms cells that proliferate and differentiate toward macrophages in response to M-CSF, overexpression of DUSP5 increased M-CSF-dependent proliferation and strongly decreased differentiation. Similarly, overexpression of DUSP5 in the multipotent EGER-Fms cells not only significantly increased M-CSF-induced proliferation and prevented macrophage differentiation but also favored granulocytic differentiation. Altogether, experiments demonstrated that DUSP5 is implicated in M-CSF signaling and suggested that it may influence myeloid cell fate.

Gab2 Promotes Colony-Stimulating Factor 1-Regulated Macrophage Expansion via Alternate Effectors at Different Stages of Development

“…The simultaneous upregulation in Erk and JNK1 phosphorylation suggests a linked mechanism, e.g., via DUSPs, many of which target both Erk and JNK. DUSP5, which is implicated in M differentiation, targets Erk but not JNK (17). In our experiments, a potential role for inducible DUSPs (e.g., DUSP1) to regulate the sustained phase is supported by the ability of AD to increase JNK1 phosphorylation in WT cells to that seen in Gab2 Ϫ/Ϫ cells without any detectable effect on the Gab2 Ϫ/Ϫ cells.…”

Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations

“…DUSP 5 is an extracellular signal-regulated kinase 1/2 (ERK1/2)-specific phosphatase that is expressed in thymocytes and T cells and induced by T-cell receptor signals and by IL-2, IL-7 and IL-15 47 . DUSP5 is shown to have roles in T-cell development, macrophage colony-stimulating factor signalling and myeloid cell fate determination 47 48. Although the significance disappeared after Bonferroni correction, rs11195128 showed better correlation with eQTL for DUSP5 (p=0.007) than SMNDC1 expression in the eQTL dataset of the GenevaGenCord Consortium (see online supplementary table S5).…”

CSF-1 Receptor Signaling in Myeloid Cells

“…4A). These include DUSP5, a negative-feedback regulator of Erk1/2, which inhibits macrophage differentiation and favors granulocytic differentiation (Grasset et al 2010), interferon-inducible gene 204 (Ifi204), which suppresses proliferation and favors differentiation (Dauffy et al 2006), and the adaptor proteins suppressor of cytokine signaling 1 (Socs1) and SKAP55-related (SKAP55R). Socs1 associates with CSF-1R pTyr-697 and pTyr721 binding sites to inhibit proliferation by an unknown mechanism (Bourette et al 2001).…”