Alternatively activated macrophages during type 2 immune responses

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Type 2 immune responses operate under varying conditions in distinct tissue environments and are crucial for protection against helminth infections and for the maintenance of tissue homeostasis. 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. We are utilizing technological advances in genomics to generate new insights into the molecular heterogeneity of different developmental lineages of macrophages activated by type 2 cytokines. By using computational biology approaches to integrate complex multiparameter data, we are investigating how genetic and environmental heterogeneity contributes to the varying magnitude and quality of the type 2 immune response during infection and how this may affect macrophage function. 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 wanted to determine the molecular basis of chromatin remodeling in response to IL-4 stimulation in tissue resident and monocyte derived macrophages. By using ATAC-seq, we found that IL-4 activation of different lineages of peritoneal macrophages in mice is accompanied by lineage specific chromatin remodeling in regions enriched with binding motifs of the pioneer transcription factor PU.1. While the PU.1 motif is similarly associated with remodeling of both macrophages from a tissue resident or monocyte origin, the different lineages had specific DNA shape features and predicted co-factors flanking this motif. We then used 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 can be regulated through differences in DNA shape, without direct disruption of PU.1 motifs. Based on these findings, we proposed a model whereby DNA shape features of stimulation-dependent genomic elements contribute to differences in the accessible chromatin landscape of macrophages on different genetic backgrounds that may contribute to phenotypic variations in immune responses. We are now testing this model 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. 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 such as atherosclerosis. With our collaborators, we have been characterizing macrophages in the aorta of mice that are undergoing regression for atherosclerosis and have found that Type 2 cytokines are critical for resolving the inflammation in the aorta. We recently found that Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis. Additionally, we found also a link between these Type 2 macrophages and regulatory T cells in promoting atherosclerosis regression. This provides an example of how studying the macrophage response to parasites can also provide insights into other chronic inflammatory diseases.