Macrophages in Nematode Infection: Regulators, Effectors or Healers?

Macrophages are cells found in abundance in all tissues of the body that participate in a wide range of essentials functions through their ability to respond to signals in the local environment. T cells, which orchestrate the immune response to infection, are a key source of these signals. In response to microbial infections, T cells produce signals that ?classically-activate? macrophages to become very effective at killing intracellular bacteria. In contrast, when an individual is infected with worms T cells produce signals that ?alternatively-activate? macrophages. The function of alternatively activated macrophages (AAMac) is poorly understood but data suggests they are involved in dampening down inflammation and mediating wound repair. The possibility that they also act as cells that can kill extra-cellular parasites such as worms has not been directly addressed. AAMac have now been found in a variety of chronic disease conditions including asthma, lung fibrosis and cancer but their role has not been clearly defined. We propose to address 1) whether AAMac have direct anti-worm function, 2) whether they induce regulatory pathways associated with chronic infection and 3) whether they mediate repair of wounds caused by tissue-migrating worms. By focussing on the normal function of these cells during worm infection we hope to reveal the appropriate roles of these cells and thus address which of products of AAMac may be useful as targets in treatment of chronic diseases. These studies will also help in the design of vaccines against worms that cause debilitating infections in millions of people in the tropics.

Macrophages are a key effector cells during innate immunity and are important targets of T-cell derived cytokines during adaptive immune responses. Macrophages exposed to Th1 cytokines or microbial signals have been termed classically-activated macrophages (CAMac), while those that respond to the Th2 cytokines IL-4 and IL-13 are referred to as alternatively-activated (AAMac). The essential role of CAMac in the control of intracellular pathogens is well documented and has been extensively researched in vitro and in vivo. In contrast far less is known about AAMac function, especially in vivo. Recent data suggests AAMac have both regulatory and wound healing properties but their roles as effectors against extra-cellular pathogens is still speculative. We propose to use helminth infection models to directly address these functions in vivo. We aim to address 1) whether AAMac have direct anti-parasitic function, 2) whether they induce regulatory pathways associated with chronic infection and 3) whether they mediate tissue repair associated with tissue-migrating helminths. The AAMac vs. CAMac paradigm is unlikely to prove sufficient to explain the many functions of macrophages during Th2 mediated immune responses. Thus, our final aim is to address the in vivo signals beyond Th2 cytokines that are necessary to mediate these functions. For each of the three functional settings to be studied ? effector mechanisms, regulation, and healing ? a common set of experimental approaches will be employed. As a starting point, we will use selective depletion of macrophages at specific time points during infection. In many situations we will be able to target depletion to a particular site as well. In parallel, we will use mice in which the IL-4Ralpha is absent only on macrophages and granulocytes allowing us to address the requirement for alternative activation. Additional macrophage-specific KOs, specific inhibitors and neutralizing antibodies and reconstitution/rescue experiments will address whether a particular macrophage product or signaling pathway is required. Finally mixed bone marrow chimeric mice, will allow us to address the balance of AAMac vs. CAMac that determine disease outcome as well as the importance of antigen presentation by AAMac.