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GM-CSF: A Promising Target in Inflammation and Autoimmunity.

ABSTRACT: The cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), was firstly identified as being able to induce in vitro the proliferation and differentiation of bone marrow progenitors into granulocytes and macrophages. Much preclinical data have indicated that GM-CSF has a wide range of functions across different tissues in its action on myeloid cells, and GM-CSF deletion/depletion approaches indicate its potential as an important therapeutic target in several inflammatory and autoimmune disorders, for example, rheumatoid arthritis. In this review, we discuss briefly the biology of GM-CSF, raise some current issues and questions pertaining to this biology, summarize the results from preclinical models of a range of inflammatory and autoimmune disorders and list the latest clinical trials evaluating GM-CSF blockade in such disorders.

SUBMITTER: Lee KMC

PROVIDER: S-EPMC7605919 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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GM-CSF: A Promising Target in Inflammation and Autoimmunity.

Lee Kevin M C KMC Achuthan Adrian A AA Hamilton John A JA

ImmunoTargets and therapy 20201029

The cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), was firstly identified as being able to induce in vitro the proliferation and differentiation of bone marrow progenitors into granulocytes and macrophages. Much preclinical data have indicated that GM-CSF has a wide range of functions across different tissues in its action on myeloid cells, and GM-CSF deletion/depletion approaches indicate its potential as an important therapeutic target in several inflammatory and autoimmu ...[more]

PMID: 33150139

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GM-CSF in inflammation.

Project description:Granulocyte-macrophage colony-stimulating factor (GM-CSF) has many more functions than its original in vitro identification as an inducer of granulocyte and macrophage development from progenitor cells. Key features of GM-CSF biology need to be defined better, such as the responding and producing cell types, its links with other mediators, its prosurvival versus activation/differentiation functions, and when it is relevant in pathology. Significant preclinical data have emerged from GM-CSF deletion/depletion approaches indicating that GM-CSF is a potential target in many inflammatory/autoimmune conditions. Clinical trials targeting GM-CSF or its receptor have shown encouraging efficacy and safety profiles, particularly in rheumatoid arthritis. This review provides an update on the above topics and current issues/questions surrounding GM-CSF biology.

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Targeting the GM-CSF receptor for the treatment of CNS autoimmunity.

Project description:In multiple sclerosis (MS), there is a growing interest in inhibiting the pro-inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Rα) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Rα blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM-CSF Rα+ myeloid cells. Collectively, this study reveals a pivotal role of GM-CSF in disease relapses and the benefit of GM-CSF Rα blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS.

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The role of GM-CSF in adipose tissue inflammation.

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IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production.

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GM-CSF as a therapeutic target in autoimmune diseases.

Project description:Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been known as a hematopoietic growth factor and immune modulator. Recent studies revealed that GM-CSF also had pro-inflammatory functions and contributed to the pathogenicity of Th17 cells in the development of Th17-mediated autoimmune diseases. GM-CSF inhibition in some animal models of autoimmune diseases showed significant beneficial effects. Therefore, several agents targeting GM-CSF are being developed and are expected to be a useful strategy for the treatment of autoimmune diseases. Particularly, in clinical trials for rheumatoid arthritis (RA) patients, GM-CSF inhibition showed rapid and significant efficacy with no serious side effects. This article summarizes recent findings of GM-CSF and information of clinical trials targeting GM-CSF in autoimmune diseases.

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GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival.

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ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation.

Project description:Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.

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Autoimmunity to neuroretina in the concurrent absence of IFN-γ and IL-17A is mediated by a GM-CSF-driven eosinophilic inflammation.

Project description:IFN-γ and IL-17A can each elicit ocular autoimmunity independently of the other. Since absence of IFN-γ or IL-17A individually failed to abolish pathology of experimental autoimmune uveitis (EAU), we examined EAU development in the absence of both these cytokines. Ifng-/-Il17a-/- mice were fully susceptible to EAU with a characteristic eosinophilic ocular infiltrate, as opposed to a mononuclear infiltrate in WT mice. Retinal pathology in double-deficient mice was ameliorated when eosinophils were genetically absent or their migration was blocked, supporting a pathogenic role for eosinophils in EAU in the concurrent absence of IFN-γ and IL-17A. In EAU-challenged Ifng-/-Il17a-/- mice, ocular infiltrates contained increased GM-CSF-producing CD4+ T cells, and supernatants of retinal antigen-stimulated splenocytes contained enhanced levels of GM-CSF that contributed to activation and migration of eosinophils in vitro. Systemic or local blockade of GM-CSF ameliorated EAU in Ifng-/-Il17a-/- mice, reduced eosinophil peroxidase levels in the eye and in the serum and decreased eosinophil infiltration to the eye. These results support the interpretation that, in the concurrent absence of IFN-γ and IL-17A, GM-CSF takes on a major role as an inflammatory effector cytokine and drives an eosinophil-dominant pathology. Our findings may impact therapeutic strategies aiming to target IFN-γ and IL-17A in autoimmune uveitis.

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GM-CSF-activated STAT5A regulates macrophage functions and inflammation in atherosclerosis.

Project description:IntroductionInhibition of STAT5 was recently reported to reduce murine atherosclerosis. However, the role of STAT5 isoforms, and more in particular STAT5A in macrophages in the context of human atherosclerosis remains unknown.Methods and resultsHere, we demonstrate reciprocal expression regulation of STAT5A and STAT5B in human atherosclerotic lesions. The former was highly upregulated in ruptured over stable plaque and correlated with macrophage presence, a finding that was corroborated by the high chromosomal accessibility of STAT5A but not B gene in plaque macrophages. Phosphorylated STAT5 correlated with macrophages confirming its activation status. As macrophage STAT5 is activated by GM-CSF, we studied the effects of its silencing in GM-CSF differentiated human macrophages. STAT5A knockdown blunted the immune response, phagocytosis, cholesterol metabolism, and augmented apoptosis terms on transcriptional levels. These changes could partially be confirmed at functional level, with significant increases in apoptosis and decreases in lipid uptake and IL-6, IL-8, and TNFa cytokine secretion after STAT5A knockdown. Finally, inhibition of general and isoform A specific STAT5 significantly reduced the secretion of TNFa, IL-8 and IL-10 in ex vivo tissue slices of advanced human atherosclerotic plaques.DiscussionIn summary, we identify STAT5A as an important determinant of macrophage functions and inflammation in the context of atherosclerosis and show its promise as therapeutic target in human atherosclerotic plaque inflammation.

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GM-CSF primes cardiac inflammation in a mouse model of Kawasaki disease.

Project description:Kawasaki disease (KD) is the leading cause of pediatric heart disease in developed countries. KD patients develop cardiac inflammation, characterized by an early infiltrate of neutrophils and monocytes that precipitates coronary arteritis. Although the early inflammatory processes are linked to cardiac pathology, the factors that regulate cardiac inflammation and immune cell recruitment to the heart remain obscure. In this study, using a mouse model of KD (induced by a cell wall Candida albicans water-soluble fraction [CAWS]), we identify an essential role for granulocyte/macrophage colony-stimulating factor (GM-CSF) in orchestrating these events. GM-CSF is rapidly produced by cardiac fibroblasts after CAWS challenge, precipitating cardiac inflammation. Mechanistically, GM-CSF acts upon the local macrophage compartment, driving the expression of inflammatory cytokines and chemokines, whereas therapeutically, GM-CSF blockade markedly reduces cardiac disease. Our findings describe a novel role for GM-CSF as an essential initiating cytokine in cardiac inflammation and implicate GM-CSF as a potential target for therapeutic intervention in KD.

| S-EPMC5030799 | biostudies-literature

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