Alternative macrophage activation in the intestinal response to infection

• Applicant: Professor Dr. Tim Lämmermann, Ph.D., since 1/2021
• Subject Area: Immunology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 322359157

Helminth infections are associated with the development of type 2 immune responses. Macrophages are highly responsive to cues in their environment and can assume functionally distinct activation states dependent on the stimuli to which they are exposed. In helminth infections macrophages become alternatively, or M2, activated in response to the type 2 cytokines IL-4 and IL-13. IL-4 driven M2 activation is underpinned by a cell intrinsic increase in fatty acid oxidation. Functionally, M2 macrophages serve an important role in wound healing. Recent evidence has shown that adipocytes can also play a role in wound healing. This is interesting because in addition to their relationship to helminth infections, recent studies have placed type 2 immune cells at the centre of adipose tissue homeostasis. Based on these observations, we hypothesize that a mutually supportive relationship exists between M2 macrophages and adipocytes, in which each cell type is able to influence the other and that this interaction is critical for wound healing in general, but most particularly during helminth infection. It remains unexplored whether adipose tissue generation or remodelling occurs during the course of parasitic infections and whether this contributes to the integrity of affected tissues and ultimately to the quality of the immune response. Based on published findings and our own preliminary data, the overall goal of our project is to understand interactions between the immune system and adipose tissue during the response to intestinal infection with the nematode Heligmosomoides polygyrus, which naturally infects mice and is related to intestinal nematodes that infect humans. We hypothesize that in response to H. polygyrus infection, type 2 immunity promotes the local development of adipose tissue to support the repair of damaged intestinal tissue. Our project will focus on the relationship between macrophages within the intestinal wall, the peritoneal cavity and adipose tissue in defining the broader events that orchestrate this response to infection. To address this goal we will use mutant mice carrying conditional inducibe gene deletions and an array of immunologic, metabolic and parsitologic assays to assess changes in type 2 immunity, adiposity, macrophage migration, intestinal wound healing and resitance to intestinal parasitic infection. Our specific aims are: 1) To determine whether the expansion of peritoneal fat during infection is linked to type 2 immuntiy and important for M2 macrophage activation, tissue repair and resistance to H. polygyrus, and 2) To determine whether there is a significant movement of macrophages between the peritoneal cavity and the intestine during type 2 immune responses associated with resistance to H. polygyrus.

• DFG Programme: Research Units
• Subproject of: FOR 2599: Tissue type 2 responses: Mechanisms of induction and regulation
• Ehemaliger Antragsteller: Professor Edward Pearce, Ph.D., until 12/2020