IMPC: Faithful to the worm - Oasl1 mediated control of M(IL-4) activation and plasticity in helminth infection

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Macrophages are important cells of the immune system, centrally involved in defence against pathogens like bacteria and parasites, but also in wound healing, embryonic development and regulation of body fat storage. To be able to deal with such a diverse range of tasks, macrophages adopt specific activation characteristics dependent on cues in their environment (e.g. bacterial molecules, signals of the immune system etc.). However, circumstances may change, a wound may become infected for example, and macrophages are able to alter their activation status according to the newly arising challenge. On the other hand this flexibility has to be tightly regulated to avoid inconsistent or too short-lived activation. The mechanisms controlling this plasticity of macrophage activation are not well understood, and identifying and potentially utilizing these mechanisms for therapeutic approaches would be of great benefit. Many human disorders including cancer, metabolic syndrome and atherosclerosis have been associated with 'incorrect' activation of macrophages. Thus, being able to manipulate activation of macrophages may open up new therapeutic approaches in these and other diseases.

Recent research suggests that the capacity of macrophages to switch activation status is dependent on the expression of a cell signalling
molecule called interferon regulatory factor 7 (Irf7). Inhibition of Irf7 prevents the adoption of pro-wound healing activity by macrophages from an initial inflammatory activation state during spinal cord injury. Additionally, suppression of Irf7 prevents macrophages from changing from a wound healing phenotype to an anti-bacterial, inflammatory activation status in cell culture experiments. Thus, Irf7 seems to form a crucial lynchpin at the centre of macrophage activation switching, allowing changes in activation in both directions. So suppression of Irf7 may be a way to ensure faithfulness of the macrophage activation status in the context of complex environments like in infection. Interesting new data from our laboratory suggests that, during chronic parasitic worm infections, macrophages show high expression of a known suppressor of Irf7 called 2'-5' oligoadenylate synthetase-like 1 (Oasl1). Oasl1 reduces Irf7 activity by inhibiting the formation of new Irf7 protein within the cell. As a consequence, macrophages lacking Oasl1 show abnormal levels of Irf7 and de-regulated activation patterns. The consequences of loss of Oasl1 in parasitic worm infections or on macrophage activation faithfulness have not yet been addressed. Thus, we aim to identify the role of Oasl1 in macrophage activation as found during parasitic worm infections, also termed M(IL-4). Moreover, we will determine the consequences of loss of Oasl1 on the maintenance of the M(IL-4) activation status as well as the capacity of these cells to change their activation status to new stimuli. Lastly, we will test the effect of Oasl1 deficiency on the outcome of worm infections as well as the role of macrophage activation plasticity in a model of consecutive worm - bacterial co-infection in which macrophages normally undergo a transition in activation state. Taken together we aim to gain insight into the mechanisms controlling macrophage activation in an attempt to identify potential new therapeutic approaches for diseases such as cancer or metabolic disorders.