Immune-tissue crosstalk

Immune cells are ubiquitous, residing in every part of our body, particularly in our barrier tissues that interface with the environment. Healthy skin and gut, for example, are home to ~80 billion and 50 billion immune cells, respectively. These cells patrol our barriers for threats and respond rapidly to invaders. Beyond their pathogen-killing function, burgeoning evidence supports a role for immune cells in communicating with tissues to promote their health, aid in repair, and manage inflammatory reactions.

Our lab is decoding the lexicon of immune-tissue communication in repair, infection, inflammation and cancer. In skin repair, we uncovered a novel communication axis between resident Type 17 lymphocytes and wound epithelia (Konieczny, Xing, et al. Science, 2022). We found that damaged epithelia are unable to optimally activate HIF1α, even in the presence of wound hypoxia. Type 17 immune cells gather at the wound edge and secrete IL-17A to directly activate HIF1α in wound-edge epithelia, initiating a program of glycolysis to fuel repair. These findings have profound implications for cellular adaptation to hypoxia in complex tissue microenvironments in various damage-associated diseases, including non-healing wounds, cancers, and inflammatory conditions.

We examined the role of our newly identified IL-17A-HIF1α epithelial-immune axis in inflammatory skin diseases, exploring how epithelial and immune cells jointly fuel their pathology in chronic disease (Subudhi, Konieczny, et al. Immunity, 2024). In this study, we identified a therapeutically targetable metabolic circuit underlying the pathology of inflammatory diseases such as psoriasis, driven by IL-17A. We found that IL-17A from Type 17 cells triggers HIF1α and glycolysis to fuel epithelial pathology. In turn, glycolytic epithelia produce lactate, which drives IL-17 production from Type 17 cells. Interrupting this circuit in immune cells or epithelia completely prevents the development of disease.

This example of crosstalk between immunity and epithelia illustrates how communication pathways that mediate physiological responses to damage are co-opted pathologically in inflammatory diseases. We continue to explore how immune cells communicate with epithelia, fibroblasts, endothelia, neurons, and other tissue constituents to systematically map the language of inflammation and define novel therapeutic targets in diseases underwritten by inflammation and tissue damage.