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GM-CSF-facilitated dendritic cell recruitment and survival govern the intestinal mucosal response to a mouse enteric bacterial pathogen.

ABSTRACT: Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes dendritic cell (DC) differentiation and survival in vitro. However, its role in host defense at the intestinal mucosa is unknown. We report that infection with the mouse enteric pathogen, Citrobacter rodentium, increased colonic GM-CSF production and CD11c(+) DC recruitment. After infection, GM-CSF(-/-) mice had fewer mucosal CD11c(+) DCs, greater bacterial burden, increased mucosal inflammation and systemic spread of infection, decreased antibody responses, and delayed pathogen clearance. This defective mucosal response was rescued by GM-CSF administration to GM-CSF(-/-) mice and mimicked by CD11c(+) DC depletion in wild-type animals. Diminished mucosal DC numbers in infected GM-CSF(-/-) mice reflected decreased DC recruitment and survival, with the recruitment defect being related to a failure to upregulate epithelial cell production of the DC chemoattractant, CCL22. Thus, GM-CSF produced in the intestinal mucosa acts to enhance host protection against an enteric bacterial pathogen through regulating recruitment and survival of DCs.

SUBMITTER: Hirata Y

PROVIDER: S-EPMC2919780 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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GM-CSF-facilitated dendritic cell recruitment and survival govern the intestinal mucosal response to a mouse enteric bacterial pathogen.

Hirata Yoshihiro Y Egea Laia L Dann Sara M SM Eckmann Lars L Kagnoff Martin F MF

Cell host & microbe 20100201 2

Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes dendritic cell (DC) differentiation and survival in vitro. However, its role in host defense at the intestinal mucosa is unknown. We report that infection with the mouse enteric pathogen, Citrobacter rodentium, increased colonic GM-CSF production and CD11c(+) DC recruitment. After infection, GM-CSF(-/-) mice had fewer mucosal CD11c(+) DCs, greater bacterial burden, increased mucosal inflammation and systemic spread of infection, ...[more]

PMID: 20159620

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Project description:Stem cell factor (SCF), the ligand of c-kit, is a key cytokine for hematopoiesis. Hematopoietic precursors express c-kit, whereas differentiated cells of hematopoietic lineage are negative for this receptor, with the exception of NK cells, mast cells, and a few others. While it has long been recognized that dendritic cells (DCs) can express c-kit, several questions remain concerning the SCF/c-kit axis in DCs. This is particularly relevant for DCs found in those organs wherein SCF is highly expressed, including the bone marrow (BM). We characterized c-kit expression by conventional DCs (cDCs) from BM and demonstrated a higher proportion of c-kit+ cells among type 1 cDC subsets (cDC1s) than type 2 cDC subsets (cDC2s) in both humans and mice, whereas similar levels of c-kit expression were observed in cDC1s and cDC2s from mouse spleen. To further study c-kit regulation, DCs were generated with granulocyte-macrophage colony-stimulating factor (GM-CSF) from mouse BM, a widely used protocol. CD11c+ cells were purified from pooled non-adherent and slightly adherent cells collected after 7?days of culture, thus obtaining highly purified BM-derived DCs (BMdDCs). BMdDCs contained a small fraction of c-kit+ cells, and by replating them for 2?days with GM-CSF, we obtained a homogeneous population of c-kit+ CD40hi MHCIIhi cells. Not only did BMdDCs express c-kit but they also produced SCF, and both were striking upregulated if GM-CSF was omitted after replating. Furthermore, a small but significant reduction in BMdDC survival was observed upon SCF silencing. Incubation of BMdDCs with SCF did not modulate antigen presentation ability of these cells, nor it did regulate their membrane expression of the chemokine receptor CXCR4. We conclude that the SCF/c-kit-mediated prosurvival circuit may have been overlooked because of the prominent use of GM-CSF in DC cultures in vitro, including those human DC cultures destined for the clinics. We speculate that DCs more prominently rely on SCF in vivo in some microenvironments, with potential implications for graft-versus-host disease and antitumor immunity.

Project description:IntroductionEndogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.MethodsWe reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.ResultsWe discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.DiscussionWe identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

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GM-CSF-facilitated dendritic cell recruitment and survival govern the intestinal mucosal response to a mouse enteric bacterial pathogen.

Publications

GM-CSF-facilitated dendritic cell recruitment and survival govern the intestinal mucosal response to a mouse enteric bacterial pathogen.

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