Macrophages in Crohn's Disease: lnnate immune cellular and molecular mechanisms driving intestinal inflammation and fibrosis

Sammanfattning: Macrophages and their interactions with the lamina propria and luminal microenvi-ronment are crucial in the pathogenesis of Crohn´s disease (CD), a chronic inflamma-tory disease with a strong inflammatory innate immune involvement. Therefore, in-terpreting macrophage activity in the intestinal microenvironment may identify treatment targets beneficial for at least a subgroup of patients. The overall aim of this thesis was to establish innate immune cellular and molecular mechanisms driving intestinal inflammation and fibrosis in CD. In more detail, it was aimed to determine the inflammasome components and TREM-1 receptor expression in CD in relation-ship to macrophage phenotypes, as well as to evaluate the effects of the CD fecal microenvironment on macrophages and fibroblasts phenotypes. The first paper showed that inflammasome component expression in CD was location- and cell-specific, and MEFV and NLRP3 inflammasome expression in ileal CD was attributed to the accumulation of immature macrophages. The second paper demonstrated that TREM-1 expression was higher in CD and attributed to increased numbers of imma-ture macrophages increase in CD, defined as CD14+CD11c+HLA-DRint/high, as well as lamina propria microenvironment changes in CD. The third paper established that the CD fecal microenvironment polarize the in vitro tissue-resident macrophages into a more pronounced anti-inflammatory phenotype while induce pro-inflammatory but no fibrosis-related changes on intestinal fibroblasts. Overall, this thesis concludes that the increase of inflammasome and TREM-1 ex-pression on macrophages, and the influence of fecal microenvironment on macro-phages might be potential targets for treating CD. Forthcoming studies should aim to provide functional understanding and identify therapeutic targets in larger patient cohorts to meet the needs for improved treatments.