Pancreas resident macrophage-induced fibrosis has divergent roles in pancreas inflammatory injury and PDAC 

Baer, J.M. et al. (BioRxiv) doi: 10.1101/2022.02.09.479745

Keywords

  • Tissue resident macrophages

  • Pancreatic ductal adenocarcinoma

  • Pancreatitis

  • Fibrosis

  • Lineage tracing 

  • Single-cell sequencing

 

Main Findings

  • Tissue resident macrophages (TRMs) are initially derived from the yolk sack and maintain homeostasis of tissues. They can also be replaced by monocyte-derived macrophages, but no matter the origin, they can maintain their numbers by self-renewal. In some tissues, such as the lung, most TRMs are monocyte-derived, whereas in the liver, they are almost exclusively of embryonic origin.  

  • TRMs can repopulate tissues independently of monocytes to maintain homeostasis and in response to injury (Hashimoto et al 2013) 

  • In this preprint, Baer et al sought to elucidate the role of TRMs and MDMs in both pancreatitis and in pancreatic ductal adenocarcinoma (PDAC); two pathologies characterized by pancreas injury and inflammation driven by myeloid cells, albeit with little therapeutic options 

  • First, they establish that macrophages and acinar-to-ductal metaplasia (ADM) is increased in both human and murine samples of pancreatitis and PDAC as compared to normal pancreas

  • To determine the source of these macrophages, they use two lineage tracing models of cerulean-induced pancreatitis and find an increase in both embryonically-derived macrophages and HSC-derived macrophages with a larger fold-change in embryonically-derived macrophages

  • They leverage their second model to specifically label all TRMs since both the yolk-sac and bone-marrow can be sources of TRMs in the pancreas, and find that following induction of pancreatitis both TRM expansion and MDM infiltration occurs highlighting that self-renewed embryonically-derived macrophages and monocyte-derived macrophages both contribute to macrophage repopulation in the pancreas in response to injury

  • Comparing macrophages from the two origins using bulk RNA-seq, they find that embryonic-derived macrophages (termed eMacs) upregulate genes related to ECM remodeling, whereas bone marrow derived macrophages upregulate antigen presentation and T cell activation gene modules in normal pancreas, pancreatitis and PDAC 

  • However, location and time in tissue along with cell ontogeny is a better delineator of phenotype than ontogeny alone, as single-cell sequencing and subsequent clustering of macrophages of both origins revealed that most clusters consist of both eMacs and HSC-macrophages. This indicates that that both cell origin and tissue location dictate cellular phenotype, as previous found (Lavin et al 2014). Notably, they identified Lyve1 as a marker of a more pro-fibrotic phenotype, as Lyve1hi cells (mostly of embryonic origin), expressed gene modules related to ECM remodeling, and CXC3CR1hi macrophages (mostly derived from monocytes), expressed antigen presentation and inflammatory gene modules, which mapped well with human macrophage expression signatures 

  • Overall, their study showed that TRMs drive fibrosis and ECM deposition to repair pancreas after pancreatitis but play tumor promotive role in PDAC

Limitations

  • Acute and chronic pancreatitis have different characteristics and immune composition, so differentiating the two pathologies may show different roles of TRMs 

  • It would be interesting to see the interplay between TRMs and other immune cells such as T cells 

  • Immunotherapies directed at macrophages are being evaluated in the cancer clinic, such as CCR2 and CSF1/CSF1R inhibitors to deplete tumor associated macrophages, or CD40 agonists to push macrophages toward an immunostimulatory phenotype. These therapies can stimulate immune activation and thereby synergize with checkpoint immunotherapies that reverse immunosuppression. Their depletion strategy using aCSF1 to deplete TRMs has the potential to be translated as a therapy for early PDAC. However, PDAC is often diagnosed in late stages, so it will be interesting to see the role in early versus late PDAC, as its pro-tumor role is more prominent in early stages and depletion can be a viable a therapeutic option in early stages but its role in late stages warrants further exploration. Additionally, coopting TRMs in pancreatitis may improve outcomes for these patients, so investigating TRMs treatments in this setting has great potential 

Significance/Novelty

 

  • This preprint showed that TRMs in the pancreas are both of embryonic and bone marrow origin. However, tissue location is the primary dictator of role and function of these macrophages. Importantly, TRMs induce fibrosis and ECM remodeling but a novel finding is that this is beneficial for the host during pancreatitis in order to repair the tissue, but can be coopted by pancreatic tumors to prevent regression in the host. 

  • They focus on pancreas which is a unique tissue in that TRMs are both embryonically derived and monocyte-derived as compared to other tissues

  • Sophisticated genetic models that confirm previous findings in a new context and can be coopted in more studies and their rich sequencing data can pave the way for further exploration of the role of TRMs in the pancreas 

Credit

Reviewed by Miriam Saffern as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology  (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM). You can follow her on Twitter.