Alternatively activated macrophages during type 2 immune responses

National Institute Of Allergy And Infectious Diseases

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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 resemblance to work with our collaborators on B cell responses. How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.