Stress signaling in the interaction between innate and adaptive immunity in Multiple Sclerosis

• Applicants: Privatdozent Dr. Gerd Meyer zu Hörste; Professor Dr. Johannes Roth
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 367397604

Multiple sclerosis (MS) is driven by an uncontrolled interaction of adaptive autoimmunity and innate inflammation, but the inflammatory and (epi-)genetic mechanisms linking innate and adaptive immunity in the pathogenesis of MS are purely understood. We have previously shown that S100A8/S100A9 proteins modulate the differentiation of myeloid antigen-presenting cells in a TLR4-dependent manner in the murine and the human system. Using mRNA-Seq, ChIP-Seq and ATAC-Seq analysis we have demonstrated that continuous TLR4-activation induces epigenetic changes resulting in an immune-suppressive phenotype of antigen-presenting cells. Using transgene and knock-out models we have shown that this S100-driven mechanism regulates neural inflammation in the EAE-model. In an unbiased bioinformatics approach we found a potential link of our myeloid phenotype with the genetic background of MS and other autoimmune diseases. We have thus identified a novel regulatory mechanism of antigen-driven autoimmunity through S100-TLR4 interactions.In the present proposal we will address the following questions regarding the cross-talk of myeloid cells with T cells and brain parenchyma: How does S100A9 alter myeloid cell differentiation during EAE with special focus on myeloid derived suppressor cells (MDSC) ? How do endogenous danger signals contribute to the cross-talk of MDSC and dendritic cells with autoreactive T cells and brain parenchymal cells in EAE? How does S100A8/A9 modulate autoreactive T cells in EAE? Can we identify specific leukocyte expression patterns in MS patients in response to S100A8/A9 alarmin stimulation?To achieve these goals we will analyse murine in vitro models and will investigate functional effects of candidate genes combining genetically modified myeloid cells (HoxB8 system) with novel endonucleases (CRISPR/Cas9). Biological relevance in vivo will be confirmed using various genetically modified mouse strains. Specifically, we will employ an RNA-seq approach to characterize the expression changes induced in autoreactive T cells by S100-pretreated innate immune cells both in vitro and in vivo. By generating cell type-specific deficiency of alarmin-receptors in brain parenchymal cells, we will also study the cross-talk between innate immune cells and brain cells in CNS autoimmunity in a cell-type specific fashion. We will transfer these data to human myeloid cells and we will confirm pathological relevance of our findings analysing functional alterations expression profiles and epigenetic changes in purified leukocyte populations of individual MS patients compared to controls. We will use parallel mRNA- and ATAC-Seq under strictly controlled stimulatory conditions using selected endogenous TLR4-ligands. With this approach we will define novel targets linking innate and adaptive immunity in MS.

• DFG Programme: Research Grants