Project Details
Projekt
Macrophage-intrinsic regulators of tissue type 2 inflammation
Subject Area
Immunology
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 322359157
Macrophages fulfil a multitude of regulatory and effector functions during type 2 immune responses, but the factors that govern this functional plasticity are poorly defined. Transcriptional profiles of macrophages are shaped by transcription factors and epigenetic mechanisms/ modifiers that allow for rapid responses and – in some contexts - stable reprogramming and “innate memory”. The enzyme transglutaminase-2 (TG2) and the transcription factor aryl hydrocarbon receptor (AhR) have been implicated in the regulation of type 2 immune responses, but their role in “type 2” macrophage activation and function has remained obscure. We have observed that macrophages derived from blood monocytes of house dust mite (HDM) allergic asthma patients or from bone marrow cells of HDM-sensitized mice show increased inflammatory gene expression and responsiveness after 7 days of in vitro culture. Strikingly, bone marrow progenitors of HDM-sensitized mice showed an increased expression of TG2 compared to progenitors from the bone marrow of naïve mice. This suggested that peripheral macrophage progenitors are stably reprogrammed during type 2 inflammation and that TG2 may play a role in this process. Given the recently reported role of TG2 in histone (H3K4me3Q5) serotonylation and transcriptional activation (in neurons), we aim to investigate whether a myeloid/ hematopoietic TG2 deficiency results in altered gene expression in type 2 activated macrophages in vivo during helminth infection or allergic airway inflammation (AAI) triggered by HDM. We also aim to determine whether differences in gene expression in macrophages from asthma patients and from HDM-sensitized or helminth infected mice correlate with H3K4me3Q5 and other histone marks and/ or chromatin accessibility. Moreover, we have found that lack of the AhR or its immediate downstream target enzyme cytochrome P450 CYP1B1 leads to more severe AAI in two preclinical models of allergic asthma. Whereas CYP1B1 regulates AAI primarily through its expression in non-hematopoietic (epithelial) cells in both murine and human lung the AhR regulates gene expression in epithelial and myeloid cells upon stimulation. Strikingly, alveolar-like macrophages deficient for AhR fail to upregulate anti-inflammatory prostaglandins (PGE2) and leukotrienes (LTB4, LTC4, LTD4, LTE4) upon stimulation with house dust mite or LPS. Therefore, we now aim to globally profile the role of the AhR in the regulation of lipid mediator synthesis within macrophages and validate this function in settings of AAI and helminth infection in vivo/ex vivo. Both of these objectives will be addressed by next generation sequencing approaches (RNAseq, ChIPseq, ATACseq) that have been optimized for macrophages within the frame of several FOR2599 projects. In summary, we will determine the role of AhR and TG2 as key regulator of macrophage activation and reprogramming in type 2 immunity.
DFG Programme
Research Units
International Connection
Switzerland
