The Function And Mechanism Study Of Macrophage Polarization

Macrophages are heterogeneous population of innate immune cells found in all tissues and they are important to immune response.Macrophages undergo specifc differentiation in response to environmental cues.Two well-established polarized phenotypes are M1 macrophages and M2 macrophages.In the tumor microenvironment,tumor cells secreat distinct factors targering macrophages for their M2 polarization.M2 macrophages activation leads to the secretion of high amounts of Arginasel,Ym1,Fizzl,or IL-10 and low levels of IL-12,involving in tumor promotion,immune regulation and inhibition of inflammatory reaction.Main signaling regulating M2 polarization is IL-4R-JAK1-STAT6 signal pathway.M2 macrophage plays significant role in modulating tumor microenvironment but with very few studies in the mechanism of proteins regulating macrophage polarization.Rho GTPases are key regulators of cytoskeleton and thus control migration,division,morphogenesis and other aspects of cell physiological process.RHOBTB3 is an atypical Rho GTPase that contains a Rho GTPase-related domain near its N terminus and 2 BTB domains near its C terminus which makes RHOBTB3 act as adaptor in CULLIN3 dependent ubiquitin ligase complexes mediating substrate degradation.RHOBTB3 regulates cell cycle,vesicular transport and so on,but we have no idea about its function in cell division.Expression of RHOBTB3 has been found moderately but significantly decreased in various subtypes of carcinomas.It is worth further studing the function and mechanism of RHOBTB3 in regulating macrophage polarization in tumor microenvironment.Herein,we find that macrophages without RHOBTB3 express high levels of Arg1,Fizz1 and Yml,phosphorylation of JAK1 and STAT6 also increases after IL-4 stimulation.Besides,RHOBTB3 blocks the interaction between JAK1 and IL-4R.In addition,we find that macrophages show lower RHOBTB3 mRNA levels after IL-4 treatment.In conclusion,we deduce that tumor derived IL-4 in tumor microenvironment may decrease the expression of RHOBTB3 in macrophages,followed relieving the blockage between IL-4R and JAK1,increasing the phosphorylation of STAT6 and promoting M2 macrophage polarization.These studies provide the function and mechanism study of RHOBTB3 in regulating macrophage polarization.It is worth further studying about whether RHOBTB3 acts as a potential tumor suppressor by regulating macrophage polarization.