Deficiency of IκB Kinase ß in Myeloid Cells Reduces Severity of Experimental Autoimmune Encephalomyelitis.

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. IκB kinase ß (IKKß) is a kinase that modulates transcription of inflammatory genes. To investigate the pathogenic role of IKKß in MS, we developed strains in which IKKß was conditionally ablated in myeloid cells and established active or passive EAE in these animals. Deficiency of IKKß 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 IKKß 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 IKKß-deficient EAE mice released less IL-17, interferon-γ, and granulocyte-macrophage colony-stimulating factor after treatment with myelin peptide than splenocytes from IKKß wild-type EAE mice. Thus, deficiency of myeloid IKKß attenuates the severity of EAE by inhibiting both the neuroinflammatory activity and the activation of encephalitogenic T lymphocytes. These results suggest IKKß may be a potential target for MS patients, especially when neuroinflammation is the primary problem.