Amlexanox attenuates experimental autoimmune encephalomyelitis by inhibiting dendritic cell maturation and reprogramming effector and regulatory T cell responses.

BACKGROUND: Amlexanox (ALX), a TBK1 inhibitor, can modulate immune responses and has anti-inflammatory properties. To investigate its role in regulating the progression of experimental autoimmune encephalomyelitis (EAE), we studied the effect of ALX on the maturation of dendritic cells (DCs) and the responses of effector and regulatory T cells (Tregs). METHODS: In vitro, bone marrow-derived DCs (BMDCs) were cultured and treated with ALX. Their proliferation, maturation, and their stimulatory function to induce T cells responses were detected. In vivo, the development of EAE from different groups was recorded. At the peak stage of disease, HE, LFB, and electronic microscope (EM) were used to evaluate inflammation and demyelination. Maturation of splenic DC and Th1/Th17/Treg response in the CNS and peripheral were also detected. To further explore the mechanism underlying the action of ALX in DC maturation, the activation of TBK1, IRF3, and AKT was analyzed. RESULTS: Our data indicated that ALX significantly inhibited the proliferation and maturation of BMDCs, characterized by the reduced MHCII, a co-stimulatory molecule, IL12, and IL-23 expression, along with morphological alterations. Co-culture of ALX-treated BMDCs inhibited allogeneic T cell proliferation and MOG-specific T cell response. In EAE mice, ALX significantly attenuated the EAE development by decreasing inflammatory infiltration and demyelination in the spinal cords, accompanied by reduced frequency of splenic pathogenic Th1 and Th17 cells and increased Tregs. Moreover, ALX treatment decreased Th1 and Th17 cytokines, but increased Treg cytokines in the CNS and spleen. Notably, ALX treatment reduced the frequency and expression of CD80 and CD86 on splenic DCs and lowered IL-12 and IL-23 secretion, further supporting an impaired maturation of splenic DCs. In addition, ALX potently reduced the phosphorylation of IRF3 and AKT in BMDC and splenic DCs, both of which are substrates of TBK1 and associated with DC maturation. CONCLUSIONS: ALX, a TBK1 inhibitor, mitigated EAE development by inhibiting DC maturation and subsequent pathogenic Th1 and Th17 responses while increasing Treg responses through attenuating the TBK1/AKT and TBK1/IRF3 signaling.

Changes in lymphocyte subsets in patients with Guillain-Barré syndrome treated with immunoglobulin.

BACKGROUND: Guillain-Barré syndrome (GBS) is an autoimmune condition characterized by peripheral neuropathy. The pathogenesis of GBS is not fully understood, and the mechanism of how intravenous immunoglobulin (IVIG) cures GBS is ambiguous. Herein, we investigated lymphocyte subsets in patients with two major subtypes of GBS (acute inflammatory demyelinating polyneuropathy, AIDP, and acute motor axonal neuropathy, AMAN) before and after treatment with IVIG, and explored the possible mechanism of IVIG action. METHODS: Sixty-four patients with GBS were selected for our study and divided into two groups: AIDP (n = 38) and AMAN (n = 26). Thirty healthy individuals were chosen as the control group. Relative counts of peripheral blood T and B lymphocyte subsets were detected by flow cytometry analysis. RESULTS: In the AIDP group, the percentage of CD4+CD45RO+ T cells was significantly higher, while the percentage of CD4+CD45RA+ T cells was notably lower, than in the control group. After treatment with IVIG, the ratio of CD4+/CD8+ T cells and the percentage of CD4+CD45RA+ T cells increased, while the percentages of CD8+ T cells and CD4+CD45RO+ T cells decreased significantly, along with the number of CD19+ B cells. However, there were not such obvious changes in the AMAN group. The Hughes scores were significantly lower in both the AIDP and AMAN groups following treatment with IVIG, but the changes in Hughes scores showed no significant difference between the two groups. CONCLUSIONS: This study suggested that the changes in T and B-lymphocyte subsets, especially in CD4+T-lymphocyte subsets, might play an important role in the pathogenesis of AIDP, and in the mechanism of IVIG action against AIDP.

Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice.

Sulforaphane (SFN) is an organosulfur compound present in vegetables and has potent anti-oxidant and anti-inflammatory activities. This study was aimed at investigating the effect of treatment with SFN on inflammation and oxidative stress, and the potential mechanisms underlying the action of SFN in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. Treatment with SFN significantly inhibited the development and severity of EAE in mice, accompanied by mitigating inflammatory infiltration and demyelination in the spinal cord of mice. The protective effect of SFN was associated with significantly improved distribution of claudin-5 and occludin, and decreased levels of MMP-9 expression, preserving the blood-brain barrier. Furthermore, the protection of SFN was also related to decreased levels of oxidative stress in the brains of mice by enhanced activation of the Nrf2/ARE pathway and increased levels of anti-oxidant HO-1 and NQO1 expression. In addition, treatment with SFN inhibited antigen-specific Th17 responses and enhanced IL-10 responses. Our data indicated that treatment with SFN inhibited EAE development and severity in mice by its anti-oxidant activity and antagonizing autoimmune inflammation. Our findings suggest that SFN and its analogues may be promising reagents for intervention of multiple sclerosis and other autoimmune diseases.