Project Details
Projekt
Regulation of type 2 immunity mediated at the level of macrophage polarization
Applicant
Professor Dr. Peter J. Murray
Subject Area
Immunology
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 322359157
M2 macrophages are closely linked to macrophage reparative activities necessary for type 2 immunity in diverse tissue environments. IL4 and IL13 are the key type 2 immunity cytokines that induce the expression of hundreds of mRNAs in stimulated macrophages. These genes control tissue repair and wound healing functions as well as suppressing local T cell proliferation. In the past funding period we discovered that the pro-inflammatory cytokine TNF inhibited key pro-resolving M2 genes. We determined TNF’s effects are highly specific and targeted, via a transcriptional process, only a small fraction of these mRNAs were suppressed. A striking observation was that many of the mRNAs encode known proteins involved in the linked processes of wound and tissue repair and immune regulation. Therefore, the hypothesis we will test in the first part of the new proposal is that TNF’s main function in type 2 immune regulation is to selectively target a fraction of genes collectively necessary to complete the pro-resolving functions of the type 2 immune program (temporally, and in the steady state). We will focus on determining the identity and molecular mechanisms of TNF-regulated transcription factors (TF) that control gene-specific anti-M2 effects in the context of Type 2 immunity in tissues (Objective 1). Through collaborative work with FOR 2599 members, we will extend our findings to in vivo models of resolving type 2 immunity. Another pro-resolving component of immunity in tissue microenvironments is linked to key changes in the metabolic activity of immune cells via arginine metabolism. We observed that macrophages stimulated with LPS (i.e. glycolytic) increased in size, became laden with numerous large vesicles and expressed massive amounts of Arg1 relative to any other type of macrophage we had previously examined. These data are consistent with the appearance and number of Arg1+ Mac2+ macrophages found in tumors. Importantly, the accrual of Arg1 expression is linked to another type of pro-resolving macrophage linked to lactate production. Collectively, these data argue that Arg1 expression, cell death/survival and phagocytosis are linked processes necessary for tissue immunity requiring further investigation at the genetic and cell biology level. We will therefore determine how arginine metabolism controls macrophage survival and death pathways in chronic and acute inflammation that lead to resolving tissue immunity (Objective 2).
DFG Programme
Research Units
