Alternatively activated macrophages during type 2 immune responses

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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. 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. Through another collaboration, we find that helminth derived molecules can directly alter metabolism through alternatively activated macrophages in obese mice. This provides examples of how studying the macrophage response to parasites can also provide insights into other chronic inflammatory diseases. Finally, in our effort to study the role of macrophages under other stimulatory conditions, we have collaborated with Dr. Victor Torres to show that Staphylococcus aureus induces a muted host response in human blood that blunts the recruitment of neutrophils. 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.