Abstract
As macrophages exhibit a huge functional plasticity under homeostasis and pathological conditions, they have become a therapeutic target for chronic inflammatory diseases. Hence, the identification of macrophage subset-specific markers is a requisite for the development of macrophage-directed therapeutic interventions. In this regard, the macrophage-specific Folate Receptor β (FRβ, encoded by the FOLR2 gene) has been already validated as a target for molecular delivery in cancer as well as in macrophage-targeting therapeutic strategies for chronic inflammatory pathologies. We now show that the transcriptome of human macrophages from healthy and inflamed tissues (tumor; rheumatoid arthritis, RA) share a significant over-representation of the “anti-inflammatory gene set”, which defines the gene profile of M-CSF-dependent IL-10-producing human macrophages (M-MØ). More specifically, FOLR2 expression has been found to strongly correlate with the expression of M-MØ-specific genes in tissue-resident macrophages, tumor-associated macrophages (TAM) and macrophages from inflamed synovium, and also correlates with the presence of the PU.1 transcription factor. In fact, PU.1-binding elements are found upstream of the first exon of FOLR2 and most M-MØ-specific- and TAM-specific genes. The functional relevance of PU.1 binding was demonstrated through analysis of the proximal regulatory region of the FOLR2 gene, whose activity was dependent on a cluster of PU.1-binding sequences. Further, siRNA-mediated knockdown established the importance of PU.1 for FOLR2 gene expression in myeloid cells. Therefore, we provide evidence that FRβ marks tissue-resident macrophages as well as macrophages within inflamed tissues, and its expression is dependent on PU.1.
Highlights
Macrophages are phagocytic cells present in all tissues, whose huge functional plasticity allows them to drive promotion and resolution of inflammatory responses
Macrophage Colony-Stimulating Factor (M-CSF) triggers the acquisition of a characteristic gene expression profile that includes an “anti-inflammatory gene set” [19,24,25,26,27], whose presence characterizes human-tissue-resident macrophages [27,28,29,30] as well as tumor-associated macrophages (TAM) in vivo [16]
We have previously reported the existence of transcriptional overlaps between the variety of macrophage subsets that make up Tumor-Associated Macrophages (TAM) and M-CSF dependent macrophages, as both are enriched in the expression of the 170-gene “anti-inflammatory gene set” [19,29], which includes the FRβ-encoding FOLR2 gene [45]
Summary
Macrophages are phagocytic cells present in all tissues, whose huge functional plasticity allows them to drive promotion and resolution of inflammatory responses. M-CSF triggers the acquisition of a characteristic gene expression profile that includes an “anti-inflammatory gene set” [19,24,25,26,27], whose presence characterizes human-tissue-resident macrophages [27,28,29,30] as well as tumor-associated macrophages (TAM) in vivo [16]. We explore expression of FOLR2-encoded FRβ by tissue-resident macrophages in non-inflamed tissues and in TAM of various origins, and its correlation with the presence of genes commonly associated with the anti-inflammatory capacity of macrophages. We investigate the dependence of the macrophage-specific expression of FOLR2 on the ETS-domain transcription factor PU., which is essential for terminal myeloid cell differentiation [49,50] and control of expression of the M-CSF receptor [51]. FRβ is a useful marker for tissue-resident macrophages and macrophages within inflamed tissues, and that its expression correlates with and depends on the expression of the PU. transcription factor
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