Regulation of Macrophage Arginase Expression and Tumor Growth by the Ron Receptor Tyrosine Kinase

Abstract

M1 activation of macrophages promotes inflammation and immunity to intracellular pathogens, while M2 macrophage activation promotes resolution of inflammation, wound healing, and tumor growth. These divergent phenotypes are characterized, in part, by the expression of iNOS and arginase I (Arg1) in M1 vs. M2 activated macrophages, respectively. Here we demonstrate that the Ron receptor tyrosine kinase tips the balance of macrophage activation by attenuating the M1 phenotype while promoting expression of Arg1, through a Stat6-independent mechanism. Induction of the Arg1 promoter by Ron is mediated by an AP-1 site located 433 bp upstream of the transcription start site. Treatment of primary macrophages with MSP, the ligand for Ron, induces potent MAP kinase activation, upregulates Fos, and enhances binding of Fos to the AP-1 site in the Arg1 promoter. In vivo, Arg1 expression in tumor-associated macrophages (TAMs) from Ron−/− mice was significantly reduced compared with TAMs from control animals. Furthermore, we show that Ron is expressed specifically by Tie2-expressing macrophages (TEMs), a TAM subset that exhibits a markedly skewed M2 and pro-tumoral phenotype. Decreased Arg1 in TAMs from Ron−/− mice was associated with reduced syngeneic tumor growth in these animals. These findings indicate that Ron induces Arg1 expression in macrophages through a previously uncharacterized AP-1 site in the Arg1 promoter, and that Ron could be therapeutically targeted in the tumor microenvironment to inhibit tumor growth by targeting expression of Arg1

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

“…41 RON activation has previously been reported to skew macrophages to the M2 phenotype and attenuate inflammation. 42 When we compared expression levels of differentially regulated genes in our study with previously published datasets corresponding to defined M1 versus M2 states, 43 we found that RON activation did not strictly correlate with either the M1 or M2 state ( Fig S2 ). However, we found that RON activity was associated with an overall immunosuppressive state.…”

The Ron Receptor Tyrosine Kinase Regulates Macrophage Heterogeneity and Plays a Protective Role in Diet-Induced Obesity, Atherosclerosis, and Hepatosteatosis

“…Although Ron also induces expression of Dectin-1, it does not induce the full range of M2-associated genes and, in fact, inhibits IL-4 induction of Ym1 and Fizz1 in vitro, suggesting that these cells may be more reparative in nature (17). In vivo, the absence of Ron in the myeloid lineage in the tumor microenvironment inhibits tumor growth and cytotoxic CD8 + T cell activation.…”

“…The Ron receptor tyrosine kinase is expressed on tissue-resident macrophages, where it inhibits pathogen-and cytokine-induced inflammatory gene expression (12)(13)(14)(15)(16)(17). NF-kB and Stat1 promote an inflammatory phenotype in macrophages by coordinately inducing inflammatory gene expression.…”

“…Alternatively, Ron promotes some hallmarks of alternatively activated (M2) macrophage activation including the induction of Arg1 in an AP-1-dependent, Stat6-independent manner, as well as the upregulation of scavenger receptor-A and IL-b receptor antagonist (17). Although Ron also induces expression of Dectin-1, it does not induce the full range of M2-associated genes and, in fact, inhibits IL-4 induction of Ym1 and Fizz1 in vitro, suggesting that these cells may be more reparative in nature (17).…”

RON - The Con in Colorectal Carcinoma

“…RON signaling suppresses several hallmarks of M1 polarized macrophages such as iNOS, TNF-α and IL-12. As RON plays active role in attenuating the inflammatory response its expression associated with M2 macrophage sub-population [68].…”