Roles of GM-CSF in the Pathogenesis of Autoimmune Diseases: An Update

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was first described as a growth factor that induces the differentiation and proliferation of myeloid progenitors in the bone marrow. GM-CSF also has an important cytokine effect in chronic inflammatory diseases by stimulating the activation and migration of myeloid cells to inflammation sites, promoting survival of target cells and stimulating the renewal of effector granulocytes and macrophages. Because of these pro-cellular effects, an imbalance in GM-CSF production/signaling may lead to harmful inflammatory conditions. In this context, GM-CSF has a pathogenic role in autoimmune diseases that are dependent on cellular immune responses such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Conversely, a protective role has also been described in other autoimmune diseases where humoral responses are detrimental such as myasthenia gravis (MG), Hashimoto's thyroiditis (HT), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). In this review, we aimed for a comprehensive analysis of literature data on the multiple roles of GM-CSF in autoimmue diseases and possible therapeutic strategies that target GM-CSF production.

Keywords: GM-CSF; autoimmune diseases; inflammation; modulation; tolerance.

Figure 1

The role of GM-CSF in MS pathogenesis. In a GM-CSF dependent pathway, CD11b⁺CD62L⁺Ly6Chi monocytes are released and move toward the blood-brain barrier, which induces pro-inflammatory mediators and differentiation of central nervous system dendritic cells and macrophages. GM-CSF induces the expression of CCR2 on monocytes which bind to CCL-2, resulting in the migration of inflammatory cells across the BBB and into the CNS. Moreover, the proliferation and activation of microglia cells induced by GM-CSF are necessary for initiation of the disease. These cells secrete many mediators such as ROS, TNF-α, and Interleukin-1β. TNF-α influences BBB permeability, which leads to further destruction. Also, GM-CSF can boost the differentiation of M1-like macrophages and causes the production of higher levels of inflammatory cytokines such as IL-1, IL-6, and TNF α, all of which cooperate in the destruction of the myelin sheath. GM-CSF-induced expansion of CD11c⁺MHC⁺CD11b⁺CCR2⁺ myeloid cells (MdCs) population is accompanied by migration of MdCs into the CNS. GM-CSF secreted by Th17 cells is the main cytokine contributing to encephalitogenicity. IL-23 secreted by Th17 cells is necessary for the production of GM-CSF, and this cytokine causes an increase in pro-inflammatory myeloid cells. In addition, exTh17 cells produce GM-CSF, IFN-γ, and IL 17 simultaneously and play an important role in neuroinflammation. CD8⁺ T cells can also produce GM-CSF, and IL-17-producing CD8⁺ T cells (Tc17 cells) are a known source of GM-CSF. ThG cells, a subpopulation of CD4⁺ T cells, produce only GM-CSF and play an important role in neuroinflammation. Additionally, GM-CSF–expressing B cells play a significant role in inducing a pro-inflammatory phenotype of myeloid cells and in initiating an inflammatory response by producing GM-CSF. MS, Multiple Sclerosis Disease; BBB, Blood Brain Barrier; ROS, Reactive oxygen species.

Figure 2

Dual aspects of GM-CSF immunomodulatory effects. GM-CSF-induced bone marrow-derived dendritic cells, which co-express OX40L and Jagged-1 (Jag-1), expand regulatory T cells (Tregs). Also, GM-CSF is associated with a selective expansion of CD11c⁺CD8a⁻, CD103⁺, CX3CR1⁻, and CD11c⁺,CD11b⁺ DCs. The interaction of GM-CSF with CD116 on Tregs and iNKT cells improves immune tolerance. Monocyte-derived dendritic cells (MoDCs) are generated in the presence of GM-CSF and IL-4. These cells are capable of producing pro-inflammatory cytokines such as TNFa, IL-6, and IL-12. GM-CSF induces the M1 macrophages phenotype that produces inflammatory cytokines. In addition, GM-CSF is an essential factor for the secretion of IL-23 by DCs in a CCR4- dependent pathway. Th1/Th17 cells are induced by IL-23, IL-1β in mice and IL-1 β, IL-12 in humans. Furthermore, CD8⁺ T cells also express GM-CSF and a subset of these cells, called Tc17, produce IL-17 cells, TNF-α, IFN-γ, IL-21, IL-22, and GM-CSF. Treg, Regulatory T cell; iNKT, Invariant natural killer T cells; Th1/Th17, T helper 1/17 cells; TNFa, Tumor necrosis factor alpha.