IL-4)) activation, linked to wound repair and type 2 pathology 3, 4, 5. Although pulmonary macrophage sub-populations inhabit dramatically different anatomical sites, such as the airways and tissue parenchyma, it is not yet clear how location influences their ability to respond to type 2 inflammation. In particular, reports of M(IL-4) marker expression on lung macrophages during type 2 inflammation 6, 7, 8, 9 have involved experimental approaches that may not clearly distinguish macrophages from other myeloid cells, raising the possibility that functional differences in key macrophage sub-populations have been inadvertently overlooked. As the predominant macrophage sub-population in airways, alveolar macrophages (AlvMs) are vital for maintaining lung health and function, having a central role in clearance of debris, surfactant and apoptotic cells 10. In the absence of AlvMs, fluid build-up leads to primary pulmonary alveolar proteinosis, severe lung dysfunction and respiratory failure 11. The majority of AlvMs are thought to be derived from embryonic precursors that seed the lung tissue before birth 12 , with recent evidence suggesting that the cytokines GM-CSF and TGF-β induce PPAR-γ, a crucial transcription factor for AlvM development 11, 13, 14. During inflammation, AlvMs mediate bacterial clearance and initiate neutrophil recruitment 15 , functions that can be regulated by cytokines such as IL-10 or TGF-β, and/or the engagement of cell surface receptors such as SIRPα or CD200 16. Because clear discrimination between AlvMs and other lung macrophage sub-populations is technically challenging 17 , far less is known about the function and origin of tissue residing interstitial macrophages (IntMs). Although IntMs may comprise up to three separate subpopulations 18 , earlier work may have mistakenly identified them as AlvMs, monocytes or dendritic cells (DCs). Mucosal environments like the lung play a major role in determining both development and function of macrophages 19 , though many of the factors that shape such processes remain unclear, particularly in type 2 inflammation. Lung macrophage upregulation of M(IL-4) markers during parasite-mediated type 2 responses is promoted by environmental factors such as surfactant protein A (SP-A) and engagement of TAM receptors during clearance of apoptotic cells 20, 21. Here we show that lung macrophage subsets, particularly AlvMs, were considerably less responsive to type 2 inflammation than macrophages from other tissues. We demonstrate that this muted phenotype was conferred by the lung environment, and was independent of potential negative regulators such as CD200-CD200R, surfactant protein D (SP-D), mucin 5b (Muc5b) or the host microbiota. Hypo-responsive AlvMs had an altered metabolic profile compared to IL-4-responsive peritoneal exudate cell macrophages (PECMs), and were unable to upregulate glycolysis in situ. Results AlvMs are unresponsive to IL-4 in vivo To better understand how pulmonary macrophages respond during type 2 inflammation, we utilized MerTK, CD64,...

Although the growth factor progranulin was discovered more than two decades ago, the functional receptor remains elusive. Here, we discovered that EphA2, a member of the large family of Ephrin receptor tyrosine kinases, is a functional signaling receptor for progranulin. Recombinant progranulin bound with high affinity to EphA2 in both solid phase and solution. Interaction of progranulin with EphA2 caused prolonged activation of the receptor, downstream stimulation of mitogen-activated protein kinase and Akt, and promotion of capillary morphogenesis. Furthermore, we found an autoregulatory mechanism of progranulin whereby a feed-forward loop occurred in an EphA2-dependent manner that was independent of the endocytic receptor sortilin. The discovery of a functional signaling receptor for progranulin offers a new avenue for understanding the underlying mode of action of progranulin in cancer progression, tumor angiogenesis, and perhaps neurodegenerative diseases.