Figure 3: Signaling Pathways Governing the Polarization of MDSC Subsets. (A) LPS (a TLR4 ligand), IFN-γ, IL-4, and IL-13 are present in different pathological situations. LPS and IFN-γ trigger activation of ERK, NK- κB and STAT1, leading to M-MDSC skewing to M1 cells, characterized by an up-regulation of M1 hallmark genes, iNOS and TNF-b. In contrast, IL-4 and IL-13 induce activation of STAT3/5 and M-MDSC skewing to M2 cells, defined by an up-regulation of M2 related genes, arginase and IL-10 (32, 36, 37, 50- 53). PIR-A and PIR-B are highly expressed in MMDSC in a paired manner (72, 73). Upon ligand binding, PIR-A/Fc-γR complex is activated, resulting in enhanced M1 pathway. M1 pathway is thought to antagonize M2 pathway. The PIR-A ligands can activate PIR-B, leading to inhibition of M1 and M2 pathways (42). (B) Similar to Figure 3A, signals from LPS/IFN-γ and IL-4/IL-13 can dictate G-MDSC polarization into G1 and G2 cells, respectively. Both cell types are characterized by G1 hallmarks (TNF-a, Fas, ICAM-1, and ROS) and G2 hallmarks (arginase, IL-10 and CCL2/5), respectively. TGF-b is known as a negative regulator of G-MDSC polarization (44-46). Upon TGF-b binding in most cell types, TGF-bRII/RI dimer forms and activates SMAD2/3, leading to the increase of SMAD7 expression and NF-κB inhibition (74). Current data support the concept that TGF-b inhibits G1 pathway but promotes G2 pathway. It is still unclear whether and how SAMD2/3 and SMAD7 mediated TGF-b-mediated G1/G2 polarization. Arrow (thin line) and inhibitory sign (thick line) indicate promotion and suppression, respectively.