Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen

Abstract

The STAT3 signaling pathway is required for early Th17 cell development, and therapies targeting this pathway are used for autoimmune disease. However, the role of STAT3 in maintaining inflammatory effector Th17 cell function has been unexplored. Th17ΔSTAT3 mice, which delete STAT3 in effector Th17 cells, were resistant to experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Th17 cell numbers declined after STAT3 deletion, corresponding to reduced cell cycle. Th17ΔSTAT3 cells had increased IL-6–mediated phosphorylation of STAT1, known to have antiproliferative functions. Th17ΔSTAT3 cells also had reduced mitochondrial membrane potential, which can regulate intracellular Ca2+. Accordingly, Th17ΔSTAT3 cells had reduced production of proinflammatory cytokines when stimulated with myelin antigen but normal production of cytokines when TCR-induced Ca2+ flux was bypassed with ionomycin. Thus, early transcriptional roles of STAT3 in developing Th17 cells are later complimented by noncanonical STAT3 functions that sustain pathogenic Th17 cell proliferation and cytokine production.

The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma

“…Various cytokines—but particularly IL-6—are associated with the infiltration of MDSCs in the TME, which are positively correlated with glioma grade and have been shown to exert immune suppressive effects against T and NK cells through expression of enzymes such as arginase that trigger T cell arrest and apoptosis [ 112 , 113 , 114 , 115 , 116 , 117 ]. MDSCs also express IFN-α, which signals through interferon receptor type 1 (IFNAR1) to activate JAK1/STAT1 signaling, thereby upregulating expression of co-inhibitory molecule programmed death ligand-1 (PD-L1) [ 114 ].…”

Immune Microenvironment Landscape in CNS Tumors and Role in Responses to Immunotherapy

“…The inhibition of STAT3 can reactivate the immune system in the TME by promoting infiltrating DCs maturation, increasing expression of the co-stimulatory molecules (CD80/CD86) necessary for T cell activation, and decreasing the number of myeloid derived suppressor cells (MDSCs) in the immune microenvironment [121][122][123]. Additionally, STAT3 is a key inducer of immune suppressive cytokines (IL-10, IL-4, IL-6 and TGF-β), maintains immunosuppressive cell cross-talk [124][125][126][127][128], increases tumor infiltration by MDSCs, and induces T cell arrest and apoptosis [129][130][131][132]. Through MD-SCs secretion of INF-α and other mechanisms, STAT3 upregulates the expression of inhibitory immune checkpoints like PD-L1 on the surface of TAMs and tumor-infiltrating DCs [126,130].…”

Biomedical Applications of a Novel Class of High-Affinity Peptides

“…Because STAT3 activation is known to play an important role in the pathogenic cascade of the autoimmune disease psoriasis, we tested APT STAT3 -9R as a treatment for psoriatic skin inflammation. For transdermal delivery of topically applied aptide, we developed a novel lipid formulation that formed a stable complex with APT STAT3 -9R, yielding discoid-shaped lipid nanoparticles (DLNPs) encasing the aptide (Figure C) .…”