ABSTRACT
Reestablishing an appropriate balance between T effector cells (Teff) and Tregs is essential for correcting autoimmunity. Multiple sclerosis (MS) is an immune-mediated chronic CNS disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teffs Th1 and Th17 cells. STAT3 is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a potentially novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4+ T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest that selective inhibition of STAT3 by the small molecule LLL12b recalibrates the effector and regulatory arms of CD4+ T responses, representing a potentially clinically translatable therapeutic strategy for MS.
Subject(s)
Autoimmunity , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , STAT3 Transcription Factor/drug effects , T-Lymphocytes, Regulatory/immunology , Animals , Anthraquinones/pharmacology , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation , Demyelinating Diseases/drug therapy , Demyelinating Diseases/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Female , Humans , Male , Mice , Mice, Inbred C57BL , Sulfonamides/pharmacology , T-Lymphocytes, Regulatory/drug effects , Th17 Cells/immunologyABSTRACT
B lymphocyte-induced maturation protein (Blimp-1) is a transcription factor that regulates effector/memory B cells and CD8 T cells. Here we show that Blimp-1 is expressed in both Th1 and Th17 cells in vitro and highly expressed in effector/memory myelin-specific CD4 T cells in experimental autoimmune encephalomyelitis (EAE) mice. The immunized Blimp-1 conditional knockout mice have a significantly delayed disease onset but enhanced disease severity during the effector phase compared to their wild-type littermates, suggesting that Blimp-1 is a unique transcription factor with distinct roles in the regulation of myelin-specific CD4 T cells during priming and effector phase of EAE.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Positive Regulatory Domain I-Binding Factor 1/immunology , Animals , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , Encephalomyelitis, Autoimmune, Experimental/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Positive Regulatory Domain I-Binding Factor 1/metabolismABSTRACT
Daily moderate exercise (DME) and stress management are underemphasized in the care of patients with lupus nephritis (LN) due to a poor comprehensive understanding of their potential roles in controlling the inflammatory response. To investigate these effects on murine LN, disease progression was monitored with either DME or social disruption stress (SDR) induction in NZM2410/J mice, which spontaneously develop severe, early-onset LN. SDR of previously established social hierarchies was performed daily for 6 days and DME consisted of treadmill walking (8.5 m/min for 45 min/day). SDR significantly enhanced kidney disease when compared to age-matched, randomly selected control counterparts, as measured by histopathological analysis of H&E staining and immunohistochemistry for complement component 3 (C3) and IgG complex deposition. Conversely, while 88% of non-exercised mice displayed significant renal damage by 43 weeks of age, this was reduced to 45% with exercise. DME also reduced histopathology in kidney tissue and significantly decreased deposits of C3 and IgG complexes. Further examination of renal infiltrates revealed a macrophage-mediated inflammatory response that was significantly induced with SDR and suppressed with DME, which also correlated with expression of inflammatory mediators. Specifically, SDR induced IL-6, TNF-α, IL-1ß, and MCP-1, while DME suppressed IL-6, TNF-α, IL-10, CXCL1, and anti-dsDNA autoantibodies. These data demonstrate that psychological stressors and DME have significant, but opposing effects on the chronic inflammation associated with LN; thus identifying and characterizing stress reduction and a daily regimen of physical activity as potential adjunct therapies to complement pharmacological intervention in the management of autoimmune disorders, including LN.
