FOR2599Project 1

Regulation of type 2 immunity mediated at the level of macrophage polarization

Peter J. Murray, Max-Planck-Institut für Biochemie, Martinsried

Image of a Schistosome granuloma (worm egg in the middle) surrounded by macrophages and other immune cells. The section was stained with a specific antibody to Arginase-1, a hallmark protein of type 2 immunity. The counter-regulation of Arginase-1 by TNF was one of the starting points of the proposed research.

Summary

M2 macrophages are involved in related elements of type 2 immunity in tissues. The best association between M2 macrophages and type 2 immunity is promotion of wound healing and tissue repair. However, M2 macrophages also have anti-helminthic activity, and have potent suppressive effects on lymphocyte proliferation and cytokine production. The cellular and molecular mechanisms controlling the quantity and longevity of M2 macrophage responses in type 2 inflammation and immunity in different tissues remain largely uncharted. In other words, what factors limit M2 macrophage number and function such that tissue homeostasis can be restored to a balanced state? We recently discovered the pro-inflammatory cytokine TNF has a vital counter-regulatory activity against M2 macrophages. In the absence of TNF, there are more M2 macrophages, and enhanced M2-associated gene expression. The main objective of this proposal is to understand the relationship between M2 macrophages and TNF. We predict the TNF-anti-M2 pathway is involved in most, if not all type 2 responses, and is aberrantly regulated in settings where type 2 responses are required but suppressed by TNF. Two related objectives about TNF and type 2 immunity will be tackled. First, we found TNF regulates type 2 cytokine production from eosinophils. Since eosinophils are central to type 2 immunity and important drivers of M2 macrophages, dissecting the link between TNF and eosinophil activity is likely to fill in gaps in knowledge about the cellular interplay in type 2 immunity. We will also begin to tackle the complexity of the effects of TNF in modulating type 2 immunity in acute and chronic inflammation, which will require close collaboration with the other research groups.