MicroRNA‐155 Deficiency Suppresses Th17 Cell Differentiation and Improves Locomotor Recovery after Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is considered to be primarily associated with loss of motor function and leads to activate diverse cellular mechanisms in the central nervous system to attempt to repair the damaged spinal cord tissue. Mir-155 has been reported to be involved in both innate and adaptive immune responses. But the role of Mir-155 in spinal cord injury is still unknown. In our current study, Mir-155 deficiency displays increased myelin sparring and enhanced SC repair process. The number of T cells, B cells and neutrophils are all significantly lower in Mir-155 À/À group than that in WT group after SCI. IL-17A-producing cells and the expression of IL-17A are markedly lower in Mir-155 À/À mice than that in WT mice. We also found higher production of IL-17 by WT CD4 + T cells than Mir-155 À/À CD4 + T cells in vitro. In our further DC-T cell coculture system, Mir-155 deficiency in DCs results in significantly less IL-17 production from T cells. Furthermore, the inhibited Th17 differentiation induced by Mir-155 deficiency is partly dependent on increased expression of SOCS1. In conclusion, our present work provides evidence to support the concept that Mir-155 deficiency suppresses Th17 cell differentiation and improves locomotor recovery after SCI.

Role of microRNA‐155 in rheumatoid arthritis

“…However, WT mice developed clinical signs of arthritis, including an increase in paw swelling and decrease in grip strength. Histologic analysis showed severe joint inflammation in WT mice, characterized by marked infiltration of the synovial membrane with inflammatory cells, local bone destruction as well as osteoclasts attached to the bone erosions in the hind paws . Synovial TNF‐α expression, serum levels IL‐6, IL‐17, vascular epithelial growth factor (VEGF), IL‐2, IFN‐γ and the chemokines C‐X‐C chemokine ligand 1 (CXCL1), CXCL9 were markedly reduced in miR‐155 −/− mice compared with WT mice .…”

“…Synovial TNF‐α expression, serum levels IL‐6, IL‐17, vascular epithelial growth factor (VEGF), IL‐2, IFN‐γ and the chemokines C‐X‐C chemokine ligand 1 (CXCL1), CXCL9 were markedly reduced in miR‐155 −/− mice compared with WT mice . CD4 + T cells from miR‐155 −/− mice produced significantly less IL‐17, IL‐22 and IFN‐γ than did CD4 + T cells from WT mice, and WT mice immunized with collagen generated strongly high titers of collagen‐specific IgG2a and IgG1 than did miR‐155 −/− mice . When the arthritogenic serum was intraperitoneally injected into WT and miR‐155 −/− mice, both groups of animals developed arthritis, but the grip strength scores were significantly higher in miR‐155 −/− mice compared to WT mice, accompanied by a significant reduction in the extent of bone erosions, and reduced numbers of osteoclasts in the hind paws in miR‐155 −/− mice .…”

“…miR‐155 −/− B cells led to reduced extrafollicular and germinal center responses, and immunoglobulin G1 (IgG1) antibodies production . Interestingly, overexpression of miR‐155 in activated cluster of differentiation 4 (CD4) + T cells promoted T‐helper 1 cell (Th1) differentiation, and miR‐155 −/− T cells under Th17 polarization condition revealed reduced production of the Th17 cytokines interleukin (IL)‐17 and IL‐22 . Available evidence suggested that expression of miR‐155 was abnormal in RA patients and arthritis models.…”

“…17 Interestingly, overexpression of miR-155 in activated cluster of differentiation 4 (CD4) + T cells promoted T-helper 1 cell (Th1) differentiation, 18 and miR-155 À/À T cells under Th17 polarization condition revealed reduced production of the Th17 cytokines interleukin (IL)-17 and IL-22. 19 Available evidence suggested that expression of miR-155 was abnormal in RA patients and arthritis models. In addition, functional analysis revealed that overexpression of miR-155 or miR-155 knockdown resulted in aberrant production of auto-antibodies and pro-inflammatory cytokines, which correlate with the pathogenesis of arthritis.…”

The Role of microRNA Markers in the Diagnosis, Treatment, and Outcome Prediction of Spinal Cord Injury

“…However, in miR-155 knockout mice, Basso Mouse Scale locomotor scores have been found to be higher 6 weeks after SCI compared with control groups. In addition, miR-155 knockout mice also expressed significantly lower levels of IL-17–expressing T cells, suggesting that miR-155 has a direct effect on Th17 cell proliferation after SCI via the regulation of Janus-associated kinase/signal transducer and activator of transcription (JAK/STAT) signaling by the suppressor of cytokine signaling 1 gene, SOCS1 (Table 1; Figure 7) (45, 46). …”