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Myeloid cell recruitment to the CNS: role of Ikk2 and establishment of non-myeloablative conditioning

Gladow, N;

In inflammatory diseases of the central nervous system (CNS), the activation of myeloid cells and circulating leukocytes and their recruitment to the site of inflammation plays a crucial role. In all of these inflammatory processes, the NF-κB signaling pathway is a key element. To study the role of NF-κB in myeloid cells in inflammatory CNS diseases, conditional knockout animals for IκB kinase 2, an element in the NF-κB signaling pathway, were created , under the control of the LysM promoter (IKK2mye). In vitro, a specific deletion of IKK2 was detected in monocytes, macrophages and granulocytes at the mRNA and protein level. The expression of the RFP reporter protein in monocytes, macrophages and granulocytes of LysMCretdRFP animals could be confirmed in vivo. In contrast, microglia showed a very low recombination efficiency in vivo. In the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, the myeloid-specific IKK2 deletion resulted in a reduced incidence and a milder disease course. In transfer experiments, in which in vitro generated MOG-specific Th17 cells led to restored EAE incidence in IKK2mye mice, the primary influence of the myeloid-specific IKK2 deletion on T cell priming could be confirmed. In contrast, no difference in the course of the disease in experimental bacterial meningitis, which was induced with Pam3CysSK4 independently of T-lymphocytes, could be found between IKK2mye and control animals.

Myeloid cells from the bone marrow can migrate into the CNS under inflammatory conditions. Otherwise, however, conditioning, e.g. by radiation or treatment with chemotherapeutic agents such as busulfan, is required. In the present dissertation, we have established a new model of non-myoloablative conditioning that allows recruitment of myeloid cells from the bone marrow to the brain. Selective cranial irradiation (HI) with 11 Gy was associated with lower blood chimerism than total body irradiation (TBI), but a lower CNS immune response was also found. The mRNA expression of the cytokines CCL2, CXCL10 and CCL5 was reduced in HI mice compared to TBI mice, but higher than in non-irradiated animals. In contrast to treatment with busulfan, migration of donor cells into the lesioned facial nerve nucleus of HI mice could be detected two weeks after facial nerve axotomy (FNA). Despite the induction of CXCL10 after irradiation, there was no evidence for a role of CXCR3, the chemokine receptor of CXCL10, in the recruitment process of myeloid cells to the CNS.