RUNX3 Negatively Regulates CD36 Expression in Myeloid Cell Lines

Abstract

CD36 is a member of the scavenger receptor type B family implicated in the binding of lipoproteins, phosphatidylserine, thrombospondin-1, and the uptake of long-chain fatty acids. On mononuclear phagocytes, recognition of apoptotic cells by CD36 contributes to peripheral tolerance and prevention of autoimmunity by impairing dendritic cell (DC) maturation. Besides, CD36 acts as a coreceptor with TLR2/6 for sensing microbial diacylglycerides, and its deficiency leads to increased susceptibility to Staphylococcus aureus infections. The RUNX3 transcription factor participates in reprogramming DC transcription after pathogen recognition, and its defective expression leads to abnormally accelerated DC maturation. We present evidence that CD36 expression is negatively regulated by the RUNX3 transcription factor during myeloid cell differentiation and activation. In molecular terms, RUNX3 impairs the activity of the proximal regulatory region of the CD36 gene in myeloid cells through in vitro recognition of two functional RUNX-binding elements. Moreover, RUNX3 occupies the CD36 gene proximal regulatory region in vivo, and its overexpression in myeloid cells results in drastically diminished CD36 expression. The down-regulation of CD36 expression by RUNX3 implies that this transcription factor could impair harmful autoimmune responses by contributing to the loss of pathogen- and apoptotic cell-recognition capabilities by mature DCs.

Role of catalase in monocytic differentiation of U937 cells by TPA: hydrogen peroxide as a second messenger

“…CD36 is an integral membrane glycoprotein and a member of the scavenger receptor type B family implicated in the binding of lipoproteins, phosphatidylserine, thrombospondin-1 and the uptake of long-chain fatty acids. 25,26 In the monocytic lineage, CD36 is expressed during the late stages of differentiation in bone marrow, in circulating monocytes and in tissue-resident macrophages, and it is thought to mediate the phagocytosis of apoptotic cells and the endocytic uptake of modified lipoproteins. [27][28][29] When U937 cells were treated with 20 nM TPA, a significant induction of CD36 expression was observed at 6 h (P ¼ 0.0073), with the expression levels then increasing in a time-dependent manner similar to the CD11b expression (data not shown).…”

Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis

“…Analysis of Affymetrix expression arrays showed that expression of Runt-related transcription factor 3 (RUNX3) differed in leukocytes from ANCA patients compared with those from healthy controls (data not shown). RUNX3 has been implicated in gene regulation in a number of systems, including functioning as a tumor suppressor (27,28), developing proprioceptive neurons within the dorsal root ganglia (29,30), epigenetic silencing in CD8 + T cells (31,32), TGF-β signaling in dendritic cells (33), and causing transcriptional repression in myeloid cells (34). In ANCA patients' leukocytes, RUNX3 mRNA was significantly reduced compared with healthy controls, in contrast to the increased PR3 and MPO mRNA in the same cohorts ( Figure 3, B-D).…”

The novel RUNX3/p33 isoform is induced upon monocyte-derived dendritic cell maturation and downregulates IL-8 expression

“…This potential mechansism of action of RUNX3/p33 is in line with its ability to interact with TLE1 ( Fig. 2) and would explain why RUNX3/p44 negatively regulates CD36 expression in U937 cells (Puig-Kroger et al, 2006), whereas RUNX3/p33 overexpression leads to augmented levels of CD36 (data not shown). Besides, since VWRPY-dependent recruitment of Groucho/TLE modulates the maturation state of murine dendritic cells (Yarmus et al, 2006), RUNX3/p33 might prevent RUNX3/p44-dependent repression from certain genes during dendritic cell maturation.…”

“…Accordingly, and even in the presence of CBFb, RUNX3/p33 did not bind oligonucleotides containing well-defined RUNX-binding sites by EMSA (data not shown), thus suggesting that its potential functional capabilities might be independent of DNA-binding. Since RUNX3/p44 regulates integrin expression (Puig-Kroger et al, 2006;DominguezSoto et al, 2005aDominguezSoto et al, , 2005b, the potential transcriptional activity of RUNX3/p33 was assayed on the regulatory regions of integrin genes. Whereas, RUNX3/p44 transactivated the CD11a promoter (4.7-fold, p o0.05), RUNX3/p33 reduced the CD11a promoter activities to 80% (po0.05) ( Fig.…”

“…The relevance of RUNX factors in immune responses is further underscored by the association of single nucleotide polymorphisms within RUNX-binding sequences with susceptibility to autoimmune disorders (AlarconRiquelme, 2003), and by the contribution of the Runx1-Foxp3, Runx1-RORwt and Runx3-T-bet interactions to Th differentiation (Ono et al, 2007;Zhang et al, 2008;Djuretic et al, 2007). RUNX1 and RUNX3 directly regulate numerous lymphoid and myeloid lineage-specific genes, including those encoding germ-line IgA1, T-cell receptor subunits, GM-CSF, M-CSF receptor, IFN-g and IL-4 and the adhesion molecules CD11a (Puig-Kroger et al, 2003) and CD36 (Puig-Kroger et al, 2006). RUNX3 is highly expressed in hematopoietic cells, and murine Runx3 has been shown to regulate TGF-b-mediated dendritic cell function and maturation (Fainaru et al, , 2005.…”