Alternatively activated macrophages during type 2 immune responses

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

Macrophages are a critical immune cell in Type 2 responses for killing and expelling parasites, as well as repairing tissue damage and resolving the inflammatory response against the parasites. The type 2 cytokine interleukin-4 (IL-4) activates macrophages to adopt distinct phenotypes associated with clearance of helminth infections and tissue repair, but the phenotype depends on the cellular lineage of these macrophages. We are using the natural genetic variation between C57BL/6 and BALB/c mouse strains to perform point-mutation studies to indicate that accessibility of these IL-4 induced regions that can be regulated epigenetically. We are now testing this system with a larger range of stimulation conditions, different strains of inbred mouse line macrophages and examining secondary responses that may be altered by the chromatin remodeling. Interestingly, we find that the background of the mice affects NF-kB activity in response to IL-4 stimulation. This bears some resemblance to work with our collaborators on B cell responses. While our studies have centered around macrophages induced by type 2 cytokines during helminth infections, these alternatively activated M2 macrophages are found in other disease conditions including bacterial infections such as Staphylococcus aureus. We previously identified a population of stem cell-like proliferating myeloid cells within inflamed tissues that could serve as a reservoir for tissue macrophages to adopt different activation states depending on the microenvironment. By single-cell RNA sequencing, we identified a cluster of BIRC5+ myeloid cells that expanded in the liver during chronic infection with either the parasite Schistosoma mansoni or the bacterial pathogen Staphylococcus aureus. In the absence of tissue-damaging toxins, S. aureus infection does not elicit these BIRC5+ cells. Deletion of BIRC5 from CX3CR1-expressing cells results in improved survival during S. aureus infection. Hence the combination of single-cell RNA sequencing and genetic fate-mapping CX3CR1+ cells revealed a toxin-dependent pathogenic role for BIRC5 in myeloid cells during S. aureus infection. Hence, the approaches we are utilizing to study macrophage activation can be applied to different stimulatory conditions and disease settings to better understand the role of macrophages and other innate cells in regulating immune responses.