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Transcriptional profile of WT and Mmp10-/- bone marrow-derived macrophages after infection with Pseudomonas aeruginosa

ABSTRACT: Several members of the matrix metalloproteinase (MMP) family control specific immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed in numerous tissues after injury; however, little is known of its function. Here, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and in cultured bone marrow-derived macrophages (BMDM). Whereas all wildtype mice were alive at 48 h post-infection, all Mmp10–/– mice had greater weight loss and died or reached euthanasia criteria with no defect in bacterial clearance. Rather, macrophage numbers in infected Mmp10–/– lungs were about 3-4-fold greater than in wildtypes. Demonstrating that the protective effect of MMP10 was due its production by macrophages, adoptive transfer of wildtype BMDM normalized infection-induced weight loss in Mmp10–/– recipients to wildtype levels. In vivo, the expression of several M1 macrophage markers were elevated and M2 markers reduced in Mmp10–/– lungs, and we saw similar differences between M1-activated wildtype and Mmp10–/– BMDM. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10–/– BMDM long after they downregulated in wildtype cells. These results indicate that MMP10 serves a beneficial role in response to infection by moderating the pro-inflammatory response of infiltrating macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE78175 | GEO | 2016/09/01

SECONDARY ACCESSION(S): PRJNA312835

REPOSITORIES: GEO

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Project description:The domestic pig (Sus scrofa) provides a large animal model for human innate immune responses and inflammation that is also economically important in its own right. Results: We demonstrate that macrophages can be harvested from 3 different compartments of the pig (lungs, blood and bone-marrow), cryopreserved and subsequently recovered and differentiated in CSF-1. We have performed surface marker analysis and gene expression profiling on macrophages from these compartments, comparing 25 animals from 5 different breeds and their response to lipopolysaccharide. The results provide a clear distinction between alveolar macrophages (AM) and monocyte-derived (MDM) and bone-marrow-derived macrophages (BMDM). In particular, the lung macrophages express the growth factor, Flt1 and its ligand, VEGFA at high levels, suggesting a distinct pathway of growth regulation. We confirm that pig macrophages more closely resemble human, than mouse, in their set of LPS-inducible genes. Relatively few genes showed breed-specific differential expression, notably CXCR2 and CD302 in alveolar macrophages. In contrast, there was substantial inter-individual variation between pigs within breeds, mostly affecting genes annotated as being involved in immune responses. Conclusions: Future research will address whether such variation is heritable, and might form the basis for selective breeding for disease resistance or functional genomics. The domestic pig (Sus scrofa) provides a large animal model for human innate immune responses and inflammation that is also economically important in its own right. We demonstrate that macrophages can be harvested from 3 different compartments of the pig (lungs, blood and bone-marrow), cryopreserved and subsequently recovered and differentiated in CSF-1. We have performed surface marker analysis and gene expression profiling on macrophages from these compartments, comparing 25 animals from 5 different breeds and their response to lipopolysaccharide. The results provide a clear distinction between alveolar macrophages (AM) and monocyte-derived (MDM) and bone-marrow-derived macrophages (BMDM). In particular, the lung macrophages express the growth factor, Flt1 and its ligand, VEGFA at high levels, suggesting a distinct pathway of growth regulation. We confirm that pig macrophages more closely resemble human, than mouse, in their set of LPS-inducible genes. Relatively few genes showed breed-specific differential expression, notably CXCR2 and CD302 in alveolar macrophages. In contrast, there was substantial inter-individual variation between pigs within breeds, mostly affecting genes annotated as being involved in immune responses. Future research will address whether such variation is heritable, and might form the basis for selective breeding for disease resistance or functional genomics. 140 Affymetrix Snowball microarray were analysed from 5 different breed (DR, LR, LW, PIE and HAM). 5 pig per breed were used and cells were harvested from Lungs, blood and bone-marrow (AM, MDM and BMDM). Cells were left untreated (0h) or stimulated with LPS Salmonella enterica serotype minnesota Re 595 - 100ng/ml (7h)

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Transcriptional profile of WT and Mmp10-/- bone marrow-derived macrophages after infection with Pseudomonas aeruginosa

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