Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC.
John M BaerChong ZuoLiang-I KangAngela Alarcon de la LastraNicholas C BorcherdingBrett L KnolhoffSavannah J BognerYu ZhuLiping YangJennifer LaurentMark A LewisNan ZhangKi-Wook KimRyan C FieldsWayne M YokoyamaJason C MillsLi DingGwendalyn J RandolphDavid G DeNardoPublished in: Nature immunology (2023)
Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, 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.
Keyphrases
- extracellular matrix
- papillary thyroid
- oxidative stress
- induced apoptosis
- dendritic cells
- chronic obstructive pulmonary disease
- wound healing
- squamous cell
- south africa
- endothelial cells
- type diabetes
- quality improvement
- peripheral blood
- cell proliferation
- signaling pathway
- skeletal muscle
- cell cycle arrest
- endoplasmic reticulum stress
- pi k akt