Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Rothlin, Carla
Abstract
Programmed cell death is carried out by a wide array of molecularly executed pathways. We postulated that the ensuing tissue effector response to cellular corpses reflects this diversity in cell death modalities. Importantly, the demise of a cell does not immediately coincide with the termination of its capacity to relay information to the surrounding tissue. We have previously described that apoptotic cell death in the lung, in the context of helminth infection and an IL-4-rich environment, is sensed by macrophages to direct the resolution of inflammation and induction of a tissue repair gene expression program. In organs like the gut, however, apoptotic cell death is commonplace and integral to its homeostatic renewal. Another specific programmed cell death modality – necroptosis – has been reported in the gut in settings of non-resolving inflammation and tissue damage, such as inflammatory bowel disease (IBD). Patients with IBD exhibit severe mucosal inflammation, including lesions that fail to progress through the classical stages of wound healing. Here we report the discovery of an effector response to necroptotic corpses (NCs). Fibroblasts and macrophages, upon encounter with NCs, each displayed an excessive inflammatory response, upregulating chemokines and cytokines that amplify inflammation. Fibroblasts are the predominant stromal cells involved in tissue healing, undergoing a key transition to myofibroblasts under the influence of TGF-β. This step is a critical event in wound healing, as fibroblast extracellular matrix deposition and remodeling rebuilds the tissue and the contractile forces generated by myofibroblasts bring the apposed edges of wounds together for closure. Exposure to NCs notably prevented fibroblast-to-myofibroblast transition. Using a chemo-genetic approach to specifically trigger necroptosis in the intestinal epithelium in vivo, we also compiled an atlas of transcriptomic changes at a single-cell level and compared this to other inflammatory and resolving injury models, noting key similarities between necroptotic IEC injury and a colitis model. Taken together, these findings support an invariant code that informs effector tissue responses based on the type, context, and sensor of cell death.
Recommended Citation
Hughes, Lindsey Demaree, "Necroptotic cell death sensing directly promotes fibroblast and macrophage inflammatory effector responses" (2023). Yale Graduate School of Arts and Sciences Dissertations. 995.
https://elischolar.library.yale.edu/gsas_dissertations/995
