The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation

Abstract

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,...

Macrophages assemble! But do they need IL‐4R during schistosomiasis?

“…lung Mres) displayed muted M(IL-4) activation profiles compared to Mmono during Nippostrongylus brasiliensis infection [18]. Furthermore, this discrepancy was linked to different metabolic programs in Mres as compared to Mmono [18]. Similar differences in metabolism linked to an altered response profile of alveolar macrophages have also been observed in a model of acute lung inflammation and injury [19].…”

“…This is not limited to the liver, as it has been recently demonstrated that alveolar macrophages (i.e. lung Mres) displayed muted M(IL‐4) activation profiles compared to Mmono during Nippostrongylus brasiliensis infection . Furthermore, this discrepancy was linked to different metabolic programs in Mres as compared to Mmono .…”

Tissue Location Drives the Metabolic Re-Profiling of Macrophages

“…In type 2 cellular immune responses, such as allergy or helminth infection, IL-4 production results in the polarization of macrophages resulting in a distinct phenotype M(IL-4) characterised by the expression of arginase-1 as well as factors involved in tissue repair, and antiinflammatory mediators [14]. Using markers recently described [2,15,16], and highly specific, gating strategy to differentiate IMs and AMs, Svedberg et al [13], observed that AMs were less responsive than IMs in vivo, following systemic or local administration of IL-4. AM hyporesponsiveness to IL-4 was confirmed in mice infected with the rodent helminth Nippostrongylus brasiliensis, which elicits the potent production Immunometabolism.…”

“…https://doi.org/10.20900/immunometab20200007 Immunometabolism 3 of 8 of IL-13 and IL-4 in the lung resulting in the activation of M(IL-4) that facilitate tissue repair and provide protection against reinfection [17,18]. Svedberg et al [13], report that AMs, contrary to IMs, fail to expand or express typical markers of M(IL-4) following infection. The differential responsiveness of AM and IM to available IL-4 could result from the distinct ontogeny or environmental niche of these cells.…”

“…The differential responsiveness of AM and IM to available IL-4 could result from the distinct ontogeny or environmental niche of these cells. To address this issue, Svedberg et al [13] purified AMs from the lungs of naive mice and cultured them in vitro. Cultured AMs altered their gene expression profile and regained responsiveness to IL-4.…”