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

Abstract

Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing β-cell neogenesis and proliferation. Macrophages (M s)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 M types, designated MHC-II lo and MHC-II hi M s, the latter being predominant. MHC-II lo and MHC-II hi pancreas M s differed at the molecular level, with MHC-II lo M s being more M2-activated. After PDL, there was an early surge of Ly6C hi monocyte infiltration in the pancreas, followed by a transient MHC-II lo M peak and ultimately a restoration of the MHC-II hi M -dominated steadystate equilibrium. These intricate M 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 M proliferation. Functionally, MHC-II lo M s were more angiogenic. We further demonstrated that, at least in C-C chemokine receptor 2-KO mice, tissue M s, rather than Ly6C hi monocyte-derived M s, contributed to β-cell proliferation. Together, our study fully characterizes the M subsets in the pancreas and clarifies the complex dynamics of M s after PDL injury.Keywords: M activation r M heterogeneity r M proliferation r Pancreas inflammation Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Harry Heimberg and Prof. Jo A. Van Ginderachter e-mail: harry.heimberg@vub.ac.be e-mail: jvangind@vub.ac.be * These authors contributed equally to this study as first co-authors. * * These authors contributed equally to this study as senior co-authors.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1482-1493 Innate immunity 1483Introduction M s display a tremendous plasticity in vivo depending on their microenvironment. Their activation status has been described using the conceptual framework of M1 (classical) and M2 (alternative) activation [1], although this model oversimplifies their true plasticity. In addition to their role as immune cells, the trophic role of M s during development, tissue repair, and regeneration is becoming increasingly appreciated [1,2]. Hence, efforts are being made to dissect specialized M subpopulations and to trace their origin in situations of sterile inflammation. Although tissueresident M s were traditionally believed to originate from bloodborne monocytes, recent evidence shows that such M s develop prenatally from dedicated precursors [3,4]. During adulthood, the pool of tissue-resident M s is maintained by low-level proliferation under steady-state [5] and can expand by enhanced in situ proliferation during pathologies [6][7][8][9]. Moreover, during sterile inflammat...

Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

“…macrophages may be sufficient for this phenomenon [103]. However, to what extent monocyte-derived MHC-II lo and MHC-II hi pancreatic macrophages upon sterile inflammation resemble their steady-state embryonically-derived counterparts remains unknown, a question that is also relevant in the context of a chronic sterile inflammation such as cancer.…”

“…Under [103]. In the PDL model, M2-like macrophages were shown to contribute to beta cell proliferation [105], and, employing CCR2-deficient mice, evidence was provided that the tissue-resident A C C E P T E D M A N U S C R I P T…”

M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment

“…Mice were intravenously injected 1 minute before sacrifice with 1 mg rat anti-CD45/PeCy7 (30-F11; eBioscience) or rat IgG2b isotype control/PECy7 (eB149/10H5; eBioscience) as was described before (7,13).…”

“…To assess whether anti-M-CSFR treatment impaired the extravasation of monocytes into 3LL-R tumors, we injected anti-CD45/ PECy7 intravenously to label all intravascular hematopoietic cells (7,13) and one minute later (a time span that is too short for labeled cells to extravasate) quantified labeled versus unlabeled cancerres.aacrjournals.org Downloaded from decrease in local CCL2 production, as was demonstrated before in other tissues (7). However, when GFP þ bone marrow cells were transferred intravenously to tumor-bearing mice pretreated with anti-M-CSFR, the recruitment of GFP þ Ly6C hi monocytes into tumors was not significantly reduced compared with control mAb-pretreated mice, arguing against major chemoattractant alterations caused by anti-M-CSFR (Fig.…”

Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury

“…These data indicate that estrogen regulation of b-cell growth is mediated by ERa. Because macrophages were suggested to promote b-cell proliferation during PDL (30), we analyzed the presence of myeloid cells in untreated or TAM-treated PDL pancreas by flow cytometry (31). No shift in the 24 PDL tail vs. 20 6 10 3 10 24 PDL head, n = 3), whereas Esr2 mRNA was decreased (1.1 6 0.5 3 10 24 PDL tail vs. 18 6 2 3 10 24 PDL head, n = 3).…”