Deficiency of I kappa B Kinase beta in Myeloid Cells Reduces Severity of Experimental Autoimmune Encephalomyelitis

摘要

In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), peripherally developed myelin-reactive T Lymphocytes stimulate myeloid cells (ie, microglia and infiltrated macrophages) to trigger an inflammatory reaction in the central nervous system, resulting in demyelination and neurodegeneration. I kappa B kinase beta (IKK beta) is a kinase that modulates transcription of inflammatory genes. To investigate the pathogenic rote of IKK beta in MS, we developed strains in which IKK beta was conditionally ablated in myeloid cells and established active or passive EAE in these animals. Deficiency of IKK beta in myeloid cells ameliorated EAE symptoms and suppressed neuroinflammation, as shown by decreased infiltration of T lymphocytes and macrophages and reduced inflammatory gene transcription in the spinal cord at the peak or end stage of EAE. Myeloid deficiency of IKK beta also reduced the transcription of Rorc or Il17 genes in T Lymphocytes isolated from lymph nodes, spleen, and spinal cord of EAE mice. Moreover, cultured splenocytes isolated from myeloid IKK beta-deficient EAE mice released Less IL-17, interferon-gamma, and granulocyte-macrophage colony-stimulating factor after treatment with myelin peptide than splenocytes from IKK beta wild-type EAE mice. Thus, deficiency of myeloid IKK beta attenuates the severity of EAE by inhibiting both the neuroinflammatory activity and the activation of encephalitogenic T lymphocytes. These results suggest IKK beta may be a potential target for MS patients, especially when neuroinflammation is the primary problem.