Ziel
The mechanisms underlying lung homeostasis are of fundamental biological importance and have critical implications for the prevention of immune-mediated diseases such as asthma. We have demonstrated that lung Interstitial Macrophages (IM) exhibit a tolerogenic profile and are able to prevent and limit the development of aberrant immune responses against allergens, thus underscoring their role as crucial regulators of lung homeostasis. In addition, we have shown that IM could expand from monocyte precursors upon host exposure to bacterial unmethylated CpG-DNA, resulting in robust protection against allergic asthma. To date, however, IM have only been characterized as a bulk population in functional studies, and little is known about the tissue-instructive signals, specific transcription factors and differentiation programs which contribute to determining their identity (ID) and function, as proposed by the macrophage niche model. We have developed an innovative transgenic tool to selectively target IM which, in combination with high dimensional single cell technologies, will allow us to (1) define the precise ID of IM, i.e. their spatial organization, heterogeneity, molecular signature and the specific TF governing their differentiation and function; (2) investigate how IM ID is imprinted by the local niche to sustain lung homeostasis. Specifically, we aim to identify the epithelial cell-derived chemo-attractive signals controlling IM precursor recruitment and to elucidate the contribution of the lung cholinergic nervous system to IM ID and lung homeostasis. This research will increase our understanding of the basic mechanisms underlying the fine-tuning of tolerogenic IM and will thus provide robust foundations for novel IM-targeted approaches promoting health and preventing airway diseases in which IM (dys)functions have been implicated.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
4000 Liege
Belgien