Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins

Abstract

Macrophages are innate immune cells of dynamic phenotype that rapidly respond to external stimuli in the microenvironment by altering their phenotype to respond to and to direct the immune response. The ability to dynamically change phenotype must be carefully regulated to prevent uncontrolled inflammatory responses and subsequently to promote resolution of inflammation. The suppressor of cytokine signaling (SOCS) proteins play a key role in regulating macrophage phenotype. In this review, we summarize research to date from mouse and human studies on the role of the SOCS proteins in determining the phenotype and function of macrophages. We will also touch on the influence of the SOCS on dendritic cell (DC) and microglial phenotype and function. The molecular mechanisms of SOCS function in macrophages and DCs are discussed, along with how dysregulation of SOCS expression or function can lead to alterations in macrophage/DC/microglial phenotype and function and to disease. Regulation of SOCS expression by microRNA is discussed. Novel therapies and unanswered questions with regard to SOCS regulation of monocyte-macrophage phenotype and function are highlighted.

Keywords: IL-4 and IL-13; M1 macrophage; M2 macrophages; dendritic cells; differentiation; macrophage; macrophages; suppressor of cytokine signaling proteins.

Figure 1

Structures of suppressor of cytokine signaling (SOCS) family members and known inducers in monocytes/macrophages and DCs. The SH2 domain is highly conserved across all SOCS members and binds phosphorylated tyrosine (pY) resides on target proteins. The kinase inhibitory region (KIR) of SOCS1 and SOCS3 acts as a pseudosubstrate to block JAK activation. The KIR inhibits the catalytic activity of JAKs by binding to the activation loop of the catalytic domain through both its KIR and SH2 domains. The SOCS box interacts with a complex containing elongin B, elongin C, cullin-5, RING-box-2 (RBX2), and E2 ligase. SOCS box-containing molecules function as E3 ubiquitin ligases and mediate the degradation of proteins that they associate with through their amino-terminal regions. SOCS proteins target the entire cytokine-receptor complex, including Janus kinase (JAK) proteins and SOCS protein themselves, for proteasomal degradation. GH, growth hormone.

Figure 2

SOCS1 and SOCS3 are potent regulators of cytokine signaling and macrophage polarization through multiple mechanisms [adapted from Ref. (11)]. Macrophages are M1 polarized in response to a number of TLR ligands and cytokines. Both SOCS1 and SOCS3 regulate TLR-4 responsiveness through the inhibition of JAK2, MAL, and NF-κB in the case of SOCS1 and through the inhibition of TRAF6 in the case of SOCS3. SOCS1 also regulates IFN- and IL-6-driven M1 polarization by inhibiting JAK activity through the KIR pseudosubstrate domain. SOCS3 regulates IL-6-driven M1 polarization by binding of pY759 the IL-6 receptor gp130 subunit and termination of signaling. SOCS3 also binds activated STAT3 to terminate signaling. Paradoxically, SOCS3 does not inhibit IL-10 signaling because it cannot bind the IL-10 receptor, nor does it effectively bind IL-10-activated STAT3, suggesting SOCS3 binding to STAT substrate is a highly specific and the determinants of this interaction are not fully understood. SOCS3 promotes M1 polarization and regulates TGF-β-driven M2 polarization by binding and preventing nuclear translocation of SMAD3. IL-4 and IL-13 trigger two distinct M2-polarizing pathways, the STAT6 and IRS-2 pathways. SOCS3 regulates IL-4/-13-driven STAT6 activation and nuclear translocation while both SOCS1 and SOCS3 can dampen PI3K and AKT activation by targeting IRS signaling proteins for proteasomal degradation. SOCS2 regulates SOCS1 and SOCS3 expression levels through proteasomal degradation. IRS, insulin receptor substrate; JAK, Janus kinase; MAL, MyD88-adaptor-like protein; STAT, signal transducers and activators of transcription; TGF-β, transforming growth factor-β; TRAF6, TNF-receptor-associated factor 6.