Mechanisms of Type 2 immune responses and its efficacy in relation to regulation of energy expenditure

Pankaj Arora

Research output: Book/ReportPh.D. thesis

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Abstract

Understanding type 2 immune responses hold strong potential to design targeted preventive and/or therapeutic strategies aimed at either ameliorating or obviating ever-increasing metabolic complications. In the gut environment, dendritic cells are the key innate immune players that orient the host's overall immunity. Additionally, a rare small intestinal epithelial cell type called tuft cells have recently been shown to initiate innate type 2 immune responses through a conserved intestinal tuft-IL-25-type 2 innate lymphoid cells (ILC2) circuit. However, we currently lack in-depth knowledge of how these cells may regulate type 2 immune responses. Manuscript I provides a focused analysis of the immunomodulatory effects of diverse compounds, in which RNA-seq-based analyses indicates that the body fluid of the helminth Ascaris suum (helminth PCF), a potential type 2 immune-driving product, strongly inhibits the Th1 and Th17 polarizing ability of LPS+IFN-γ-matured DCs by downregulating multiple components of the TLR4 signaling pathways. In Manuscript II, we examined the temporal changes in the number and activity of small intestinal tuft cells under obesogenic settings and their relationship with small intestinal and epididymal white adipose tissue (eWAT) immune activity and the systemic metabolic phenotype. Our data demonstrate that high-fat diet (HFD) feeding resulted in a significant decrease in small intestinal tuft cell numbers, reduced expression of the intestinal type 2 tuft cell markers Il25 and Tslp and, in contrast to eWAT, small intestinal lamina propria displayed a consistent non-inflammatory phenotype. Notably, small intestinal tuft cell-derived transcripts correlated with whole-body metabolic features; especially increased expression of Serpini1, encoding the serine protease inhibitor neuroserpin, which strongly associated with body mass expansion at early time points of HFD feeding. On the contrary, in mice being morbidly obese, distinct small intestinal tuft cell markers, such as genes encoding for the GABA receptors, TSLP and IL-25 correlated inversely with body mass expansion and hyperglycemia. In a separate project, presented in Manuscript III, we explored the effects of oral supplementation of helminth PCF on metabolic and immune parameters across different metabolically active tissues. The data revealed that oral intake of PCF induced specific changes in the small intestine and eWAT that were positively associated with systems-wide immune metabolic regulations in a weight reducing direction. Importantly, oral intake of helminth PCF enhanced expression of genes involved in RUNX1-regulated pathways in small intestinal tuft cells, an increase in specific ileal innate lymphoid cells as well as increased eosinophils number in eWAT. Altogether, our studies contribute to improving our understanding of type 2 immune responses, their associations with systemic metabolic regulation and further boost our knowledge into small intestinal tuft cell biology, especially with respect to their role in relaying immune-metabolic signals, which may involve interactions with the enteric neuronal system.
Original languageEnglish
PublisherTechnical University of Denmark
Number of pages177
Publication statusPublished - 2019

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