The Role of Src Kinase Associated Phosphoprotein 2 in the Development of Inflammatory Bowel Disease and Metabolic Syndrome

The intracellular adaptor protein Src kinase-associated phosphoprotein 2 (SKAP2) plays a role in inflammatory and immune-mediated diseases by regulating intracellular signalling pathways that control cytoskeletal rearrangements, cell mobility, and immune responses. SKAP2 is highly expressed in myeloid cells, and the SNPs rs10486483 and rs7804356, located within the SKAP2 gene locus, have been associated with Crohn’s disease (CD) and type 1 diabetes (T1D), respectively. However, knowledge of SKAP2’s role in inflammation, inflammatory bowel disease (IBD), and metabolic disorders remains limited. The aim of this thesis was to identify the cell types and molecular pathways influenced by SKAP2 in the context of intestinal inflammation and metabolic syndromes. Our data demonstrate that SKAP2 is crucial for maintaining homeostasis in immune regulation, as loss of SKAP2 leads to more severe dextran sodium sulphate (DSS)-induced colitis. We show that this exacerbated intestinal inflammation in SKAP2 knockout (KO) mice is driven by a hyperactive pro-inflammatory macrophage response, which subsequently promotes excessive neutrophil activation. Moreover, we found that SKAP2 is required for proper insulin secretion by pancreatic β-cells, and that its absence impairs glucose homeostasis. As a consequent, SKAP2 KO mice develop hepatic monocyte infiltration and substantial fat accumulation. Taken together, these findings highlight an essential role for SKAP2 in regulating both intestinal immune homeostasis and pancreas β-cell function. $\textit{Full-text embargoed until: 2026-11-07}$