Schistosomiasis affects more than 200 million people worldwide. During infection, the type 2 immune response and M2 macrophages play a critical role in granuloma formation around the eggs and enable the host to tolerate the tissue damage caused by these eggs, which become embedded in the liver. We previously identified phenotypic and functional differences between M2 macrophages derived from either tissue resident macrophages or inflammatory monocytes. We also determined that the M2 macrophages in acute liver granulomas formed after infection with Schistosoma mansoni are derived from inflammatory Ly6Chigh monocytes. However, as the granulomas mature and become more organized, the inflammatory macrophages in the granuloma eventually adopt features of tissue resident M2 macrophages. This phenotypic conversion into tissue resident M2 macrophages is disrupted in mice with vitamin A deficiency, an important micronutrient deficiency in developing countries, which leads to increased morbidity during infection. The key metabolite of vitamin A, retinoic acid (RA), may therefore be essential for the normal function of macrophages in the liver. We hypothesize that RA signaling enables inflammatory macrophages around the S. mansoni egg granulomas to adopt the properties of tissue resident macrophages in the local microenvironment. In contrast to S. mansoni, other helminths (e.g. Heligmosoides polygyrus) can induce expansion of M2 macrophages from tissue-resident macrophage populations. Hence, different helminth infections induce M2 activation in macrophages of different lineages. Differences in open chromatin regions may regulate differential activation of M2 macrophages from different cellular lineages. We have investigated open regions of chromatin in the different M2 macrophages. By coupling genome-wide gene expression data with sequencing data on chromatin structure, we are uncovering the regulatory networks and identifying key transcription factors that control the differential responses to IL-4 for different lineage of M2 macrophages. We hypothesize that chromatin structure is reorganized when inflammatory macrophages around S. mansoni egg granulomas adopt properties of tissue resident M2 macrophages. Failure of this process may increase mortality during infection. In this proposal we will (Aim 1) determine the role and mechanism of action of retinoic acid (RA) in regulating conversion to a tissue resident M2 macrophages phenotype and (Aim 2) identify gene regulatory networks mediating differential M2 activation of monocyte derived M2 macrophages and tissue resident M2 macrophages, and the phenotypic conversion from inflammatory macrophages to a tissue resident phenotype. While our focus is to characterize the biology of M2 macrophages during helminth infections, our findings should be translatable to the many other sites and physiological processes whereby M2 macrophages play an important functional role (e.g. in adipose tissues, atherosclerosis, tumor microenvironments and during wound repair). Hence, the impact of these studies should be broader than just helminth infections alone.
Schistosomiasis affects more than 200 million people worldwide, with the inflammatory response to the parasite eggs causing pathology, but also being important in preventing tissue damage. Macrophages are a key cell type in this inflammatory response and our major goal is to understand how macrophages are regulated during infection. The results should identify novel pathways and targets that regulate macrophages in inflammatory responses, which could be translated to combating other chronic inflammatory diseases.
| Harris, Nicola L; Loke, P'ng (2017) Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection. Immunity 47:1024-1036 |
