PPARg controls proinflammatory responses in alveolar macrophages

Tissue resident macrophages are a heterogeneous population with unique functions. During steady state conditions most tissue macrophages are of embryonic origin and maintained locally. Despite their common fetal origin, tissue macrophages are able to fulfil tissue specific functions, suggesting that the local environment can modulate cell function. It has been reported that PPARg is critical for the development of macrophages in the lung. Here, we show that PPARg functions as a transcriptional repressor in alveolar macrophages. Alveolar macrophages lacking Pparg responded more strongly to LPS stimulation by producing more cytokines and phagocytosed more particles in vitro. Certain prostaglandins can act as endogenous ligands for PPARg. We show that prostaglandins were expressed in an organ-specific fashion and modulated cytokine production by alveolar macrophages as well as bone marrow-derived macrophages and monocytic U937 cells. Pparg expression was further induced in macrophages by different cytokine combinations including IL-4, IL-3 and IL-13 suggesting a global role for PPARg which can be regulated by the local environment on two levels. Lastly, repression of inflammatory genes was mediated by PPARg interacting with NFkB and STAT signalling cascades rather than direct transrepression. Therefore PPARg is a modulator of macrophage functions, that changes the inflammatory state of macrophages by regulating classical immune signalling cascades. We isolated alveloar macrophages lacking the transcription factor Pparg from Pparg-/-.LysmCre mice. As control we isolated wild type alveolar macrophages from Pparg+/-.LysmCre and Pparg-/-.LysmCre mice. Cells were isolated based on cell surface expression of SiglecF and CD11b by FACS. RNA was extracted and gene expression measured.