Tissue Resident Macrophages Drive Fibrosis During Pancreas Inflammatory Injury and Pancreatic Ductal Adenocarcinoma
Date of Award
Doctor of Philosophy (PhD)
The immune system, and especially macrophages, are central in responding to infections, as well as providing a wide array of functions in other pathologies, especially in responding to inflammation. It is established that macrophages will accumulate within tissues during inflammation, many times secreting cytokines and chemokines central to the inflammatory response. This is particularly true during pancreatitis, or inflammation of the pancreas, where it has been shown that macrophages and monocytes accumulate in the pancreas to have various roles in further promoting inflammation. It is not well established, however, whether there are divergent roles for the distinct macrophage subsets that exist within the pancreas. Recent lineage tracing studies have shown macrophages are not only derived from circulating monocytes, but that precursors during embryonic development give rise to tissue-resident macrophage (TRM) populations. We therefore set out to investigate whether TRMs display divergent phenotypes from monocyte-derived macrophages (MDMs) during pancreatitis, and how this might shape our understanding of macrophage biology, and possible therapeutic strategies, during inflammation, as well as during pancreatic ductal adenocarcinoma (PDAC). Here, we show a significant portion of macrophages that accumulated during pancreatitis and pancreatic cancer were expanded from TRMs. We further established that pancreas TRMs have a distinct extracellular matrix remodeling and growth factor signaling phenotype, that was critical for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and animal death, due to impaired acinar cell survival and recovery. In pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, namely through PDGF-PDGFR signaling, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.
Chair and Committee
Maxim Artyomov, Kory Lavine, Gregory Longmore, Jason Mills,
Baer, John, "Tissue Resident Macrophages Drive Fibrosis During Pancreas Inflammatory Injury and Pancreatic Ductal Adenocarcinoma" (2022). Arts & Sciences Electronic Theses and Dissertations. 2788.
Allergy and Immunology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons