Evaluation of the effect of GM-CSF blocking on the phenotype and function of human monocytes

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotent cytokine that prompts the proliferation of bone marrow-derived macrophages and granulocytes. In addition to its effects as a growth factor, GM-CSF plays an important role in chronic inflammatory autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Reports have identified monocytes as the primary target of GM-CSF; however, its effect on monocyte activation has been under-estimated. Here, using flow cytometry and ELISA we show that GM-CSF induces an inflammatory profile in human monocytes, which includes an upregulated expression of HLA-DR and CD86 molecules and increased production of TNF-α and IL-1β. Conversely, blockage of endogenous GM-CSF with antibody treatment not only inhibited the inflammatory profile of these cells, but also induced an immunomodulatory one, as shown by increased IL-10 production by monocytes. Further analysis with qPCR, flow cytometry and ELISA experiments revealed that GM-CSF blockage in monocytes stimulated production of the chemokine CXCL-11, which suppressed T cell proliferation. Blockade of CXCL-11 abrogated anti-GM-CSF treatment and induced inflammatory monocytes. Our findings show that anti-GM-CSF treatment induces modulatory monocytes that act in a CXCL-11-dependent manner, a mechanism that can be used in the development of novel approaches to treat chronic inflammatory autoimmune diseases.

Colony Stimulating Factors in Early Feline Infectious Peritonitis Virus Infection of Monocytes and in End Stage Feline Infectious Peritonitis; A Combined In Vivo And In Vitro Approach

“…This may represent an immediate response of the immune system to try and remove the virus. GM-CSF also induces an inflammatory profile in human monocytes; should it have a similar role in cats, this would decrease the required stimulus threshold for activation [35]. In concert, IL-6 and GM-CSF released from newly infected monocytes could increase the monocyte pool and thereby ensure that sufficient cells are available to maintain viral replication.…”

CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities

“…GM-CSF is one of those promising factors, which is secreted by CAR T-cells following activation and activates myeloid cells but does not appear to contribute to CAR-T cell function (37,65,86). In vitro inactivation of GM-CSF in CAR-T cells reduced myeloid cell-derived inflammatory cytokines (37), and in some studies GM-CSF inhibition reduced expression of some CRS associated cytokines, such as IL-6, but not IL-1b (37,65,(86)(87)(88). However, in animal studies, GM-CSF neutralization did not completely prevent inflammatory toxicities (86).…”

Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers

“…GM-CSF is also an immunomodulatory cytokine, which can promote the differentiation of monocyte/M1 type macrophages and DCs, enhance their activities and antigen presentation, and amplify the body's immune response ( 26 , 95 ). Previous studies showed that the expression level of DC gene signature in renal cell carcinoma and NSCLC tissues was positively correlated with OS ( 27 ).…”