Tissue-Resident Macrophages Play Divergent Roles in Pancreatitis and Cancer

Long-lived tissue-resident macrophages (TRM) are maintained locally, while short-lived monocyte-derived macrophages (MDM) rely on circulating monocytes to be replenished. These developmental origins can affect macrophage phenotype, but the potentially divergent roles that these phenotypically distinct macrophages play in different pathologies have not yet been fully elucidated. In this study, Baer and colleagues sought to determine the roles of TRMs and MDMs in murine models of pancreatitis and pancreatic ductal adenocarcinoma (PDAC) and showed that the accumulation of macrophages, in both pancreatitis and PDAC tissues, resulted from the expansion of TRMs. Evaluation of the roles of these macrophages during pancreas injury and cancer revealed that pancreas TRMs display distinct transcriptional phenotypes with significant enrichment in genes related to extracellular matrix (ECM) remodeling and growth factor signaling, which supports their potential contribution to fibrosis during pancreas injury. Similar phenotypes and localization were also observed in human TRMs. Investigation into the functional impact of TRMs and MDMs during pancreatitis indicated that TRMs maintain pancreas tissue integrity after acute damage, while MDMs are generally dispensable. Moreover, TRM depletion during pancreatitis did not alter acinar-to-ductal metaplasia but did reduce the number of fibroblasts as well as the ECM molecule fibronectin and led to impaired survival, suggesting that TRMs promote stromagenesis and impact pancreatitis recovery. Additionally, in the presence of TRMs, a tissue protective effect was observed, with fibroblasts upregulating genes related to collagen and ECM production, while, in the absence of TRMs, the fibrotic response was attenuated, with genes linked to an inflammatory phenotype being more highly expressed. Finally, in PDAC, TRM-driven fibrosis was shown to drive tumor progression, while depletion of TRMs attenuated fibroblast accumulation and reduced pancreatitis-induced tumor burden. In summary, this study shows that TRMs in the pancreas induce fibrosis that elicits protective effects during pancreatitis but promotes PDAC progression, suggesting that the tissue remodeling induced by TRMs promotes distinct disease outcomes that are dependent on the type of tissue injury.

Baer JM, Zuo C, Kang LI, de la Lastra AA, Borcherding NC, Knolhoff BL, et al. Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC. Nat Immunol 2023;24:1443–57.

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