Dual role of SIRPα in macrophage activation: inhibiting M1 while promoting M2 polarization via selectively activating SHP-1 and SHP-2 signal

Abstract Macrophages polarization into proinflammatory M1 or alternative M2 states, which plays a central role in inflammation and host defense, is tightly controlled by multiple regulatory molecules. Here we examined the role of signal regulatory protein α (SIRPα), which negatively regulates leukocyte responses, in regulating macrophage polarization and function. Compared to WT macrophages, macrophage obtained from SIRPα deficient (SIRPα−/−) mice demonstrated an enhanced response to M1 induction but were refractory to M2 induction, as indicated by the increased expression of M1-related markers CD86, MHC-II, iNOS, IL-1β, IL-12 and TNF-α under M1-skewed LPS/IFNγ treatment but the defective expression of anti-inflammatory mediators CD206, Arg1, IL-10 and TGFβ during IL-4 induced M2 activation. Furthermore, ligating SIRPα by CD47 extracellular domain (mCD47-AP) suppressed M1 polarization but enhanced M2 polarization in WT macrophages, whereas had no effect on SIRPα−/− macrophage polarization. Interestingly, under M1 and M2 activation, macrophage SIRPα was found to be tyrosine-phosphorylated and selectively associated with SHP-1 and SHP-2, respectively. Mechanistic studies indicated that SIRPα deficiency promoted M1 but attenuated M2 polarization of macrophages by enhancing the PI3k/Akt2 signaling pathway. Overall, our findings demonstrated for the first time that SIRPα plays an important role in modulating macrophage polarization, inhibiting M1 while promoting M2 phenotypic polarization through selectively activating SHP-1 and SHP-2 signaling.