FOR2599Project 3

Alternative macrophage activation in the intestinal response to infection

Edward J. Pearce, Max Planck Institute for Immunobiology and Epigenetics, Freiburg, and Faculty of Biology, University of Freiburg

Heligmosomoides polygyrus is an intestinal helminth parasite. Infection is initiated when larval stages of the parasite are swallowed, and invade the intestinal wall, where they become surrounded by granulomatous lesions. The immune response to the parasite is type 2 in nature.

Summary

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,which are made largely by Th2 and/or ILC2 cells.  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. In addition we will explore the nature of IL-4/IL-13 producing cells that reside in adipose tissues during infection. To address these goals 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.

Selected publications

Huang SC, Smith AM, Everts B, Colonna M, Pearce EL, Schilling JD, Pearce EJ. (2016). Metabolic Reprogramming Mediated by the mTORC2-IRF4 Signaling Axis Is Essential for Macrophage Alternative Activation. Immunity. 45(4):817-830

Kannan Y, Perez-Lloret J, Li Y, Entwistle LJ, Khoury H, Papoutsopoulou S, Mahmood R, Mansour NR, Ching-Cheng Huang S, Pearce EJ, Pedro S de Carvalho L, Ley SC, Wilson MS. (2016). TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology. PLoS Pathog. 2016 Aug 3;12(8):e1005783.

Kaiko GE, Ryu SH, Koues OI, Collins PL, Solnica-Krezel L, Pearce EJ, Pearce EL, Oltz EM, Stappenbeck TS. (2016). The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites. Cell. 2016 Jun 16;165(7):1708-20.

Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, Pearce EJ, Driggers EM, Artyomov MN. (2015).  Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 42(3):419-30.

Nascimento M, Huang SC, Smith A, Everts B, Lam W, Bassity E, Gautier EL, Randolph GJ, Pearce EJ. (2014). Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis. PLoS Pathog. 10(8):e1004282.

Huang SC, Everts B, Ivanova Y, O'Sullivan D, Nascimento M, Smith AM, Beatty W, Love-Gregory L, Lam WY, O'Neill CM, Yan C, Du H, Abumrad NA, Urban JF Jr, Artyomov MN, Pearce EL, Pearce EJ. (2014). Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol. 15(9):846-55.

Gautier EL, Ivanov S, Williams JW, Huang SC, Marcelin G, Fairfax K, Wang PL, Francis JS, Leone P, Wilson DB, Artyomov MN, Pearce EJ, Randolph GJ. (2014). Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J Exp Med. 211(8):1525-31.