Stimulus-Dependent Requirement for Granulocyte-Macrophage Colony-Stimulating Factor in Inflammation

Cook, Andrew D.; Braine, Emma L.; Hamilton, John A.

doi:10.4049/jimmunol.173.7.4643

Cited by 60 publications

(86 citation statements)

References 47 publications

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“…Similar results were obtained using GM-CSF Ϫ/Ϫ mice or C57BL/6 mice treated with anti-GM-CSF mAb. This finding of a normal early, predominantly neutrophil, response but a later defective macrophage response in K/BxN serum-transfer arthritis induced in GM-CSF Ϫ/Ϫ mice is similar to what we observed in the methylated bovine serum albumin-induced peritonitis model in these mice (22). It has been suggested that macrophages are most likely important after the initiation of K/BxN serum-transfer arthritis, being a major source of proinflammatory cytokines (45), whereas neutrophils are required in the early stage involving the vascular permeability that precedes disease onset (46).…”

Section: Discussionsupporting

confidence: 89%

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Regulation of systemic and local myeloid cell subpopulations by bone marrow cell–derived granulocyte–macrophage colony‐stimulating factor in experimental inflammatory arthritis

Cook

Turner

Braine

et al. 2011

Arthritis & Rheumatism

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Objective. Even though there are clinical trials assessing granulocyte-macrophage colony-stimulating factor (GM-CSF) blockade in rheumatoid arthritis (RA), questions remain as to how GM-CSF acts as a proinflammatory cytokine. The aims of this study on the regulation of arthritis progression by GM-CSF were to determine the source of the GM-CSF, whether there are systemic effects, the changes in synovial tissue leukocyte populations, and the arthritis model dependence on GM-CSF.Methods. Bone marrow chimeras were used to determine the source of GM-CSF required for the development of collagen-induced arthritis (CIA). The K/BxN serum-transfer model of arthritis was tested in GM-CSF ؊/؊ mice and using anti-GM-CSF monoclonal antibodies. Cell populations from arthritic mice were assessed by differential staining and flow cytometry.Results. In the CIA model, GM-CSF produced by bone marrow-derived cells was required for arthritis development. GM-CSF blockade, while ameliorating the development of CIA, was found to have systemic effects, limiting the increase in circulating Ly-6C high monocytes and neutrophils. GM-CSF blockade led to fewer synovial macrophages (both Ly-6C high and Ly-6C low ), neutrophils, and lymphocytes. In the absence of GM-CSF, K/BxN serum-transfer arthritis initially developed normally; however, the numbers of Ly-6C high monocytes and synovial macrophages (both Ly-6C high and Ly-6C low ) were again reduced, along with the peak disease severity and maintenance.Conclusion. GM-CSF is a key player in two arthritis models, participating in interactions between hemopoietic cells, both locally and systemically, to control myeloid cell numbers as well as presumably to "activate" them. These results could be useful for the analysis of current clinical trials targeting GM-CSF in patients with RA.Granulocyte-macrophage colony-stimulating factor (GM-CSF) was initially discovered by its role in the differentiation of hemopoietic precursor cells into mature granulocytes and macrophages (1); however, it can also affect mature cell function and may be considered a proinflammatory cytokine (2-4). In this context, clinical trials are in progress testing this concept in rheumatoid arthritis (RA) (4).GM-CSF is produced in vitro by a number of different cell types following exposure to various stimuli (4-8). A so-called CSF network has been proposed in which GM-CSF and other CSFs form part of a cytokinemediated hemopoietic cell-tissue cell interaction that drives chronic inflammatory reactions, for example, in joints (9). In support of this concept, several models of disease, including arthritis (10-12), multiple sclerosis Professor Hamilton has received consulting fees from MorphoSys AG and CSL, Ltd. (less than $10,000 a year). The University of Melbourne has licensed to MorphoSys AG, Germany, patented technology relating to therapeutically targeting granulocyte-macrophage colony-stimulating factor, for which licensing fees and milestone payments have been made.

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Section: Discussionsupporting

confidence: 89%

“…As to GM-CSF dependence of a particular pathology, we have found that the requirement for GM-CSF in inflammatory responses is stimulus dependent, with methylated bovine serum albumin-induced peritonitis being GM-CSF dependent, while thioglycollate-elicited peritonitis is GM-CSF independent, in relation to cell numbers (22).…”

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confidence: 98%

Regulation of systemic and local myeloid cell subpopulations by bone marrow cell–derived granulocyte–macrophage colony‐stimulating factor in experimental inflammatory arthritis

Cook

Turner

Braine

et al. 2011

Arthritis & Rheumatism

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“…This raises the possibility that the reduced eosinophilic inflammation in the GM-CSF Ϫ/Ϫ mice may be caused by the pulmonary abnormalities of these animals, rather than by a defect in allergic inflammatory reactions. However, a study on inflammation in another site, the peritoneal cavity, reported fewer eosinophils in the peritoneal lavage of GM-CSF Ϫ/Ϫ mice compared with that of WT animals (40). These findings indicate that defects in tissue eosinophilia are not limited to the lung, but are a general feature of GM-CSF Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 72%

Granulocyte-Macrophage Colony-Stimulating Factor Is Required for Bronchial Eosinophilia in a Murine Model of Allergic Airway Inflammation

Rolph

Hansbro

et al. 2008

The Journal of Immunology

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GM-CSF plays an important role in inflammation by promoting the production, activation, and survival of granulocytes and macrophages. In this study, GM-CSF knockout (GM-CSF−/−) mice were used to investigate the role of GM-CSF in a model of allergic airway inflammation. In allergic GM-CSF−/− mice, eosinophil recruitment to the airways showed a striking pattern, with eosinophils present in perivascular areas, but almost completely absent in peribronchial areas, whereas in wild-type mice, eosinophil infiltration appeared in both areas. In the GM-CSF−/− mice, mucus production in the airways was also reduced, and eosinophil numbers were markedly reduced in the bronchoalveolar lavage (BAL)3 fluid. IL-5 production was reduced in the lung tissue and BAL fluid of GM-CSF−/− mice, but IL-4 and IL-13 production, airway hyperresponsiveness, and serum IgE levels were not affected. The presence of eosinophils in perivascular but not peribronchial regions was suggestive of a cell migration defect in the airways of GM-CSF−/− mice. The CCR3 agonists CCL5 (RANTES) and CCL11 (eotaxin-1) were expressed at similar levels in GM-CSF−/− and wild-type mice. However, IFN-γ mRNA and protein were increased in the lung tissue and BAL fluid in GM-CSF−/− mice, as were mRNA levels of the IFN-γ-inducible chemokines CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-Tac). Interestingly, these IFN-γ-inducible chemokines are natural antagonists of CCR3, suggesting that their overproduction in GM-CSF−/− mice contributes to the lack of airway eosinophils. These findings demonstrate distinctive abnormalities to a model of allergic asthma in the absence of GM-CSF.

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“…Acute peritonitis was induced as described previously (3,22). On days 0 and 14, mice were injected intradermally at the base of the tail with 100 ml mBSA (1 mg/ml in CFA).…”

Section: Induction Of Acute Peritonitismentioning

confidence: 99%

Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-κB1–Dependent GM-CSF Production in CD4 T Cells

Campbell

Nieuwenhuijze

Ségura

et al. 2011

The Journal of Immunology

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Rel/NF-κB transcription factors regulate inflammatory and immune responses. Despite possible subunit redundancy, NF-κB1–deficient (Nfkb1−/−) mice were profoundly protected from sterile CD4 T cell-dependent acute inflammatory arthritis and peritonitis. We evaluated CD4 T cell function in Nfkb1−/− mice and found increased apoptosis and selectively reduced GM-CSF production. Apoptosis was blocked by expression of a Bcl-2 transgene without restoring a disease response. In contrast with wild-type cells, transfer of Nfkb1−/− or GM-CSF–deficient CD4 T cells into RAG-1–deficient (Rag1−/−) mice failed to support arthritis induction. Injection of GM-CSF into Nfkb1−/− mice fully restored the disease response, suggesting that T cells are an important source of GM-CSF during acute inflammation. In Ag-induced peritonitis, NF-κB1–dependent GM-CSF production in CD4 T cells was required for disease and for generation of inflammatory monocyte-derived dendritic cells (MoDC), but not conventional dendritic cells. MoDC were identified in inflamed synovium and draining lymph nodes during arthritis. These MoDC produced high levels of MCP-1, a potent chemoattractant for monocytes. This study revealed two important findings: NF-κB1 serves a critical role in the production of GM-CSF by activated CD4 T cells during inflammatory responses, and GM-CSF derived from these cells drives the generation of MoDC during inflammatory disease.

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Stimulus-Dependent Requirement for Granulocyte-Macrophage Colony-Stimulating Factor in Inflammation

Cited by 60 publications

References 47 publications

Regulation of systemic and local myeloid cell subpopulations by bone marrow cell–derived granulocyte–macrophage colony‐stimulating factor in experimental inflammatory arthritis

Regulation of systemic and local myeloid cell subpopulations by bone marrow cell–derived granulocyte–macrophage colony‐stimulating factor in experimental inflammatory arthritis

Granulocyte-Macrophage Colony-Stimulating Factor Is Required for Bronchial Eosinophilia in a Murine Model of Allergic Airway Inflammation

Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-κB1–Dependent GM-CSF Production in CD4 T Cells

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