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Environmental and genetic factors have been demonstrated to contribute to the development of inflammatory bowel disease (IBD). Recent studies suggested that the food additive; titanium dioxide (TiO₂) might play a causative role in the disease. Therefore, in the present study we aimed to explore the interaction between the food additive TiO₂ and the well-characterized IBD risk gene protein tyrosine phosphatase non-receptor type 2 (<i>Ptpn2</i>) and their role in the development of intestinal inflammation. Dextran sodium sulphate (DSS)-induced acute colitis was performed in mice lacking the expression of <i>Ptpn2</i> in myeloid cells (<i>Ptpn2^LysMCre</i>) or their wild type littermates (<i>Ptpn2^fl/fl</i>) and exposed to the microparticle TiO₂. The impact of <i>Ptpn2</i> on TiO₂ signalling pathways and TiO₂-induced IL-1β and IL-10 levels were studied using bone marrow-derived macrophages (BMDMs). <i>Ptpn2^LysMCre</i> exposed to TiO₂ exhibited more severe intestinal inflammation than their wild type counterparts. This effect was likely due to the impact of TiO₂ on the differentiation of intestinal macrophages, suppressing the number of anti-inflammatory macrophages in <i>Ptpn2</i> deficient mice. Moreover, we also found that TiO₂ was able to induce the secretion of IL-1β via mitogen-activated proteins kinases (MAPKs) and to repress the expression of IL-10 in bone marrow-derived macrophages via MAPK-independent pathways. This is the first evidence of the cooperation between the genetic risk factor <i>Ptpn2</i> and the environmental factor TiO₂ in the regulation of intestinal inflammation. The results presented here suggest that the ingestion of certain industrial compounds should be taken into account, especially in individuals with increased genetic risk