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Background  The ten mouse and six human members of the  Schlafen  ( Slfn ) gene family all contain an AAA domain. Little is known of their function, but previous studies suggest roles in immune cell development. In this report, we assessed  Slfn  regulation and function in macrophages, which are key cellular regulators of innate immunity.    Methodology/Principal Findings  Multiple members of the  Slfn  family were up-regulated in mouse bone marrow-derived macrophages (BMM) by the Toll-like Receptor (TLR)4 agonist lipopolysaccharide (LPS), the TLR3 agonist Poly(I∶C), and in disease-affected joints in the collagen-induced model of rheumatoid arthritis. Of these, the most inducible was  Slfn4 . TLR agonists that signal exclusively through the MyD88 adaptor protein had more modest effects on  Slfn4  mRNA levels, thus implicating MyD88-independent signalling and autocrine interferon (IFN)-β in inducible expression. This was supported by the substantial reduction in basal and LPS-induced  Slfn4  mRNA expression in IFNAR-1 −/−  BMM. LPS causes growth arrest in macrophages, and other  Slfn  family genes have been implicated in growth control.  Slfn4  mRNA levels were repressed during macrophage colony-stimulating factor (CSF-1)-mediated differentiation of bone marrow progenitors into BMM. To determine the role of  Slfn4 in vivo , we over-expressed the gene specifically in macrophages in mice using a  csf1r  promoter-driven binary expression system. Transgenic over-expression of  Slfn4  in myeloid cells did not alter macrophage colony formation or proliferation  in vitro . Monocyte numbers, as well as inflammatory macrophages recruited to the peritoneal cavity, were reduced in transgenic mice that specifically over-expressed  Slfn4 , while macrophage numbers and hematopoietic activity were increased in the livers and spleens.    Conclusions    Slfn4  mRNA levels were up-regulated during macrophage activation but down-regulated during differentiation. Constitutive  Slfn4  expression in the myeloid lineage  in vivo  perturbs myelopoiesis. We hypothesise that the down-regulation of  Slfn4  gene expression during macrophage differentiation is a necessary step in development of this lineage.

Macrophage Activation and Differentiation Signals Regulate Schlafen-4 Gene Expression: Evidence for Schlafen-4 as a Modulator of Myelopoiesis