The role of expressed sequence Aa467197 in macrophage responses to inflammation

Abstract

Chronic inflammatory diseases are one of the greatest threats to human health in the modern world, contributing to a number of debilitating disease pathologies and deaths. One of the key cell types involved in the inflammatory response are macrophages, which contribute to the initiation of inflammation through secretion of pro-inflammatory mediators and inducing neutrophil migration to affected tissues. However, they are also crucial for the resolution of inflammation by initiating and regulating the tissue remodelling response. Failure to properly induce the anti-inflammatory, tissue healing response or inadequate regulation of the pro-inflammatory response by macrophages has been identified as a cause of pathology in a number of chronic diseases. Accordingly, understanding how macrophages are polarised towards an anti-inflammatory phenotype and which factors contribute to the exertion of tissue remodelling functions is essential to develop new treatments for chronic inflammatory diseases. In the last few years, the expressed sequence Aa467197 has emerged as a candidate gene which may be involved in inducing or contributing to macrophage tissue remodelling functions, inducing a negative feedback loop in the LPS-induced inflammatory response and being one of the most highly expressed genes in macrophages which have acquired tissue remodelling functions through stimulation with IL-4. Accordingly, the aim of this thesis was to determine how Aa467197 is expressed in tissue remodelling macrophages, how Aa467197 can affect expression of tissue remodelling markers and genes related to macrophage tissue remodelling functions by using RNAseq, and how Aa467197 affects disease outcome in mouse models of colitis and schistosomiasis. The findings presented in this thesis suggest that Aa467197 may regulate macrophage polarisation early after sensing of anti-inflammatory cytokines, influencing the transcription of genes characteristic for tissue remodelling macrophages, such as Chil3 and Gata3. In addition, Aa467197 may contribute to the induction of macrophage tissue remodelling functions, including chemotaxis, blood vessel development, and angiogenesis, and may play a role in initiating pathways induced by cytoskeletal remodelling in macrophages. Finally, expression of Aa467197 may contribute to the pathogenesis of colitis through alterations in the microbiota composition, while in schistosomiasis Aa467197 contributes to monocyte infiltration and fibrosis development in the intestine as well as ARG1 expression in macrophages of infected livers. Overall, there is evidence that Aa467197 contributes to the function of tissue remodelling macrophages during intestinal inflammation, and further investigations should be performed to assess whether it may present a good target for macrophage-related therapies for chronic diseases.