Dataset Information

Incomplete deletion of IL-4R? by LysM(Cre) reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis.

ABSTRACT: Mice expressing a Cre recombinase from the lysozyme M-encoding locus (Lyz2) have been widely used to dissect gene function in macrophages and neutrophils. Here, we show that while naïve resident tissue macrophages from IL-4R?f(lox/delta)LysM(Cre) mice almost completely lose IL-4R? function, a large fraction of macrophages elicited by sterile inflammatory stimuli, Schistosoma mansoni eggs, or S. mansoni infection, fail to excise Il4r?. These F4/80(hi)CD11b(hi) macrophages, in contrast to resident tissue macrophages, express lower levels of Lyz2 explaining why this population resists LysM(Cre)-mediated deletion. We show that in response to IL-4 and IL-13, Lyz2(lo)IL-4R?(+) macrophages differentiate into an arginase 1-expressing alternatively-activated macrophage (AAM) population, which slows the development of lethal fibrosis in schistosomiasis. In contrast, we identified Lyz2(hi)IL-4R?(+) macrophages as the key subset of AAMs mediating the downmodulation of granulomatous inflammation in chronic schistosomiasis. Our observations reveal a limitation on using a LysMCre mouse model to study gene function in inflammatory settings, but we utilize this limitation as a means to demonstrate that distinct populations of alternatively activated macrophages control inflammation and fibrosis in chronic schistosomiasis.

SUBMITTER: Vannella KM

PROVIDER: S-EPMC4161449 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Publications

Incomplete deletion of IL-4Rα by LysM(Cre) reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis.

Vannella Kevin M KM Barron Luke L Borthwick Lee A LA Kindrachuk Kristen N KN Narasimhan Prakash Babu PB Hart Kevin M KM Thompson Robert W RW White Sandra S Cheever Allen W AW Ramalingam Thirumalai R TR Wynn Thomas A TA

PLoS pathogens 20140911 9

Mice expressing a Cre recombinase from the lysozyme M-encoding locus (Lyz2) have been widely used to dissect gene function in macrophages and neutrophils. Here, we show that while naïve resident tissue macrophages from IL-4Rαf(lox/delta)LysM(Cre) mice almost completely lose IL-4Rα function, a large fraction of macrophages elicited by sterile inflammatory stimuli, Schistosoma mansoni eggs, or S. mansoni infection, fail to excise Il4rα. These F4/80(hi)CD11b(hi) macrophages, in contrast to resident ...[more]

PMID: 25211233

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Project description:Macrophages (MΦs) are heterogeneous and metabolically flexible with metabolism strongly affecting immune activation. A classic response to pro-inflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, while alternative activation is primarily oxidative which begs the question of whether targeting glucose metabolism is a viable approach to control MΦ activation. We created a murine model of myeloid-specific glucose transporter GLUT1 (Slc2a1) deletion. Bone marrow derived MΦs (BMDM) from Slc2a1M-/- mice failed to uptake glucose and demonstrated reduced glycolysis and Pentose Phosphate Pathway activity. Activated BMDMs displayed elevated metabolism of oleate and glutamine, yet maximal respiratory capacity was blunted in MΦ lacking GLUT1 demonstrating an incomplete metabolic reprogramming. Slc2a1M-/- BMDMs displayed a mixed inflammatory phenotype with reductions of the classically-activated pro- and anti-inflammatory markers, yet less oxidative stress. Slc2a1M-/- BMDMs had reduced pro-inflammatory metabolites, whereas metabolites indicative of alternative activation - such as ornithine and polyamines - were greatly elevated in the absence of GLUT1. Adipose tissue MΦs of lean Slc2a1M-/- mice had increased alternative M2-like activation marker mannose receptor CD206, yet lack of GLUT1 was not a critical mediator in the development of obesity-associated metabolic dysregulation. However, Ldlr-/- mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1M-/- BMDMs may have contributed to unstable atheroma formation. Together our findings suggest that while lack of GLUT1 blunted glycolysis and PPP, MΦ were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated yet phagocytic defects hindered MΦ function in chronic diseases. Control mice are noted as WT or Slc2a1 fl/fl and myeloid GLUT1 deficient are KO or Slc2a1M-/- (LysMCre X Slc2a1fl/fl) for myeloid deficiency.

Dataset Information

Incomplete deletion of IL-4R? by LysM(Cre) reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis.

Publications

Incomplete deletion of IL-4Rα by LysM(Cre) reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis.

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