Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas

Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing β‐cell neogenesis and proliferation. Macrophages (MΦs) were recently shown to promote β‐cell proliferation after PDL, but they remain poorly characterized. We assessed myeloid cell diversity and the factors driving myeloid cell dynamics following acute pancreas injury by PDL. In naive and sham‐operated pancreas, the myeloid cell compartment consisted mainly of two distinct tissue‐resident MΦ types, designated MHC‐IIlo and MHC‐IIhi MΦs, the latter being predominant. MHC‐IIlo and MHC‐IIhi pancreas MΦs differed at the molecular level, with MHC‐IIlo MΦs being more M2‐activated. After PDL, there was an early surge of Ly6Chi monocyte infiltration in the pancreas, followed by a transient MHC‐IIlo MΦ peak and ultimately a restoration of the MHC‐IIhi MΦ‐dominated steady‐state equilibrium. These intricate MΦ dynamics in PDL pancreas depended on monocyte recruitment by C‐C chemokine receptor 2 and macrophage‐colony stimulating factor receptor as well as on macrophage‐colony stimulating factor receptor‐dependent local MΦ proliferation. Functionally, MHC‐IIlo MΦs were more angiogenic. We further demonstrated that, at least in C‐C chemokine receptor 2‐KO mice, tissue MΦs, rather than Ly6Chi monocyte‐derived MΦs, contributed to β‐cell proliferation. Together, our study fully characterizes the MΦ subsets in the pancreas and clarifies the complex dynamics of MΦs after PDL injury.

[1]  J. Ehses,et al.  Resident Macrophages Mediate Islet Amyloid Polypeptide–Induced Islet IL-1β Production and β-Cell Dysfunction , 2014, Diabetes.

[2]  K. Prasadan,et al.  M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7 , 2014, Proceedings of the National Academy of Sciences.

[3]  S. Levy,et al.  Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration. , 2014, Cell metabolism.

[4]  Jessica L. Cohen,et al.  Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. , 2014, Cell metabolism.

[5]  Ansuman T. Satpathy,et al.  Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. , 2014, Immunity.

[6]  D. Hume,et al.  IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1 , 2013, The Journal of experimental medicine.

[7]  F. Ginhoux,et al.  Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. , 2013, Immunity.

[8]  P. Taylor,et al.  Tissue-resident macrophages , 2013, Nature Immunology.

[9]  M. Czech,et al.  Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes , 2013, Nature Medicine.

[10]  P. Taylor,et al.  Distinct bone marrow-derived and tissue resident macrophage-lineages proliferate at key stages during inflammation , 2013, Nature Communications.

[11]  Thomas A. Wynn,et al.  Macrophage biology in development, homeostasis and disease , 2013, Nature.

[12]  F. Ginhoux,et al.  Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. , 2013, Immunity.

[13]  K. Prasadan,et al.  TGFβ Receptor Signaling Is Essential for Inflammation-Induced but Not β-Cell Workload–Induced β-Cell Proliferation , 2013, Diabetes.

[14]  J. Ahnfelt-Rønne,et al.  Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas , 2013, Cell Death and Disease.

[15]  Jianchun Chen,et al.  CSF-1 signaling mediates recovery from acute kidney injury. , 2012, The Journal of clinical investigation.

[16]  Amin R. Mazloom,et al.  Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages , 2012, Nature Immunology.

[17]  H. Okada,et al.  Survivin Is Required for Beta-Cell Mass Expansion in the Pancreatic Duct-Ligated Mouse Model , 2012, PloS one.

[18]  F. Ginhoux,et al.  Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac–derived macrophages , 2012, The Journal of experimental medicine.

[19]  J. Pollard,et al.  A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells , 2012, Science.

[20]  Daniel G. Anderson,et al.  Origins of tumor-associated macrophages and neutrophils , 2012, Proceedings of the National Academy of Sciences.

[21]  E. Pamer,et al.  Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1 , 2011, The Journal of experimental medicine.

[22]  F. Finkelman,et al.  Local Macrophage Proliferation, Rather than Recruitment from the Blood, Is a Signature of TH2 Inflammation , 2011, Science.

[23]  P. De Baetselier,et al.  Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. , 2010, Cancer research.

[24]  S. Gordon,et al.  The myeloid 7/4-antigen defines recently generated inflammatory macrophages and is synonymous with Ly-6B , 2010, Journal of leukocyte biology.

[25]  Leonore A. Herzenberg,et al.  Two physically, functionally, and developmentally distinct peritoneal macrophage subsets , 2010, Proceedings of the National Academy of Sciences.

[26]  P. Libby,et al.  Identification of Splenic Reservoir Monocytes and Their Deployment to Inflammatory Sites , 2009, Science.

[27]  J. Pollard.  Trophic macrophages in development and disease , 2009, Nature Reviews Immunology.

[28]  C. Mathieu,et al.  Pancreatic Duct Cells in Human Islet Cell Preparations Are a Source of Angiogenic Cytokines Interleukin-8 and Vascular Endothelial Growth Factor , 2008, Diabetes.

[29]  L. Williams,et al.  Discovery of a Cytokine and Its Receptor by Functional Screening of the Extracellular Proteome , 2008, Science.

[30]  J. DeGregori,et al.  Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration , 2008, Diabetes.

[31]  K. Zaret.  Faculty Opinions recommendation of Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. , 2008 .

[32]  R. Scharfmann,et al.  β Cells Can Be Generated from Endogenous Progenitors in Injured Adult Mouse Pancreas , 2008, Cell.

[33]  N. Van Rooijen,et al.  Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis , 2007, The Journal of experimental medicine.

[34]  E. Unanue,et al.  In CD4+ T-cell-induced diabetes, macrophages are the final effector cells that mediate islet beta-cell killing: studies from an acute model. , 2006, The American journal of pathology.

[35]  P. De Baetselier,et al.  Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. , 2006, Blood.

[36]  R. F. Luco,et al.  IA1 is NGN3‐dependent and essential for differentiation of the endocrine pancreas , 2006, The EMBO journal.

[37]  H. Drexhage,et al.  Macrophages in the murine pancreas and their involvement in fetal endocrine development in vitro , 2005, Journal of leukocyte biology.

[38]  H. Drexhage,et al.  Dendritic cells and macrophages are essential for the retention of lymphocytes in (peri)-insulitis of the nonobese diabetic mouse: a phagocyte depletion study , 2005, Laboratory Investigation.

[39]  J. Pollard,et al.  Insulin cell mass is altered in Csf1op/Csf1op macrophage‐deficient mice , 2004, Journal of leukocyte biology.

[40]  N. L. Hayes,et al.  Stem Cells: The Promises and Pitfalls , 2001, Neuropsychopharmacology.

[41]  Johannes Gerdes,et al.  The Ki‐67 protein: From the known and the unknown , 2000, Journal of cellular physiology.

[42]  H. Jun,et al.  The Role of Macrophages in T Cell–mediated Autoimmune Diabetes in Nonobese Diabetic Mice , 1999, The Journal of experimental medicine.

[43]  L. Bouwens,et al.  Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats , 1995, Diabetologia.

[44]  R. Atkins,et al.  Deoxyspergualin suppresses local macrophage proliferation in rat renal allograft rejection. , 1994, Transplantation.

[45]  V. Ferrans,et al.  Alveolar macrophage replication. One mechanism for the expansion of the mononuclear phagocyte population in the chronically inflamed lung. , 1984, The Journal of clinical investigation.

[46]  P. Carmeliet,et al.  Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. , 2014, Cancer research.

[47]  N. Van Rooijen,et al.  Liposomes for specific depletion of macrophages from organs and tissues. , 2010, Methods in molecular biology.