Key Research Interests and Expertise

Journal of Immunology cover

The long-standing research interest of this lab is the study of mucosal tissue, in particular that of the lung and the gut during health and inflammation.   Experimentally we use an integrated approach; our research traverses epithelial stem cells, the innate immune system and commensal bacteria.

The key to a healthy mucosa is the maintenance of the epithelial barrier, which takes place by the division of epithelial stem cells, their differentiation into different epithelial cell types and the renewal of the epithelium. During homeostasis the epithelium forms a tight barrier preventing direct contact of the external environment i.e. microbes with underlying immune cells so preventing an inflammatory response.

Our research (Skoczek et al. 2014) has shown that immune cells underlying the epithelium are critical regulators of homeostasis in the gut.  Using gut organotypic culture we have shown that in health the intact crypt epithelial barrier first detects any changes in bacterial composition of the gut lumen and then rapidly recruits underlying Ly6C+ monocytes (via the MyD88 signalling pathway) from the smooth muscle and submucosal layers to the crypt epithelial stem cell niche. This physical repositioning of monocytes is significant because it causes temporary alterations in the rate renewal of the epithelium thus allowing fine tuning of immune responses to maintain health and barrier function.  We have also shown that monocytes help maintain the number of crypt epithelial stem cells in vivo; further supporting our hypothesis that immune-epithelial interactions are important in the maintenance of tissue homeostasis.

During inflammation the epithelial barrier is compromised, which allows bacteria to interact directly with the body’s immune system and an inflammatory response occurs. Our hypothesis is that the highly regulated homeostatic interaction between monocytes and epithelial stem cells we observed is dysregulated during inflammation.

Homeostasis is a tightly regulated process requiring finely-tuned complex interactions between different cell types, growth factors / cytokines and their receptors.  Another hypothesis in my lab is that the signaling pathways of these factors also play a role in stem cell driven tissue renewal during homeostasis or inflammation and that these factors may be epithelial-derived (autocrine) or immune cell-derived (paracrine).

Recent work published also in the Journal of Immunology has demonstrated a previously unidentified role for autocrine IL-6 signaling in the maintenance of the small intestinal crypt stem cell niche, through the differential expression of the IL-6 receptor and downstream STAT3 signaling in Paneth cells and the Wnt signaling pathway.

Dagmara Skczoek (former PhD student)
Petr Walcyzsko (Postdoc)
Andy Goldson (Postdoc)

Vicki Jeffery (current PhD student)

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