Myelin specific T cells induce inflammasome activation in microglia in zones of axonal degeneration

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) and associated with infiltration of myelin specific T cells and elevated cytokine expression. Recently, we showed that myelin specific T cells, producing high levels of interferon-gamma and interleukin-17 can be targeted to zones of axonal degeneration where they enhance microglial clearance of myelin debris. To better understand which cytokines are elevated in response to myelin specific T cells, we used mRNA microarray analysis to compare the transcript profile in hippocampi from mice with adoptively transferred proteolipid protein specific T cells combined with an axonal lesion (TPlp + AxL) and mice with axonal lesion (AxL) with 2 day post lesion (dpl) survival. Thereby, we identified 1447 differently expressed transcripts and by performing DAVID and AmiGO analysis the Interleukin-1 (IL-1) signaling pathway showed the most upregulated transcripts. We discovered that IL-1a, IL-1b, IL-1 receptor antagonist (ra) and Caspase-1 mRNA, are significantly upregulated in response to myelin specific T cells. qPCR analysis confirmed the microarray data at 2dpl and additionally showed increased expression of three IL-1 receptor ligands in TPlp + AxL mice. The qPCR data for IL-1a and IL-1b mRNA expression were confirmed by in situ hybridization (ISH). Immunohistochemical stainings showed expression of IL-1b in the hippocampus of TPlp + AxL mice, but not in AxL mice. Double ISH showed that IL-1b and CD11b mRNA are co-expressed in microglia. Ongoing studies aim to show that IL-1b and NLRP3 of the inflammasome are co-expressed with CD11b in microglia in TPlp + AxL mice. These results can lead to a better understanding of the role of inflammasome activation for disease progression in patients with MS.