GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches

Abstract

Therapeutics against coronavirus disease 2019 (COVID-19) are urgently needed. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a myelopoietic growth factor and pro-inflammatory cytokine, plays a critical role in alveolar macrophage homeostasis, lung inflammation and immunological disease. Both administration and inhibition of GM-CSF are currently being therapeutically tested in COVID-19 clinical trials. This Perspective discusses the pleiotropic biology of GM-CSF and the scientific merits behind these contrasting approaches.

Fig. 1. GM-CSF and inflammation.

The immune response, including granulocyte–macrophage colony-stimulating factor (GM-CSF) upregulation, can be triggered when an antigen induces a ‘danger’ signal from a host cell. During this response, GM-CSF can act locally in inflamed tissue to induce the survival, proliferation and/or differentiation of myeloid cells, such as monocytes/macrophages and neutrophils. More specifically, GM-CSF can potentially do the following: activate mature myeloid cells to a pro-inflammatory phenotype with enhanced cytokine (for example, IL-1, IL-6 and tumour necrosis factor (TNF)) and chemokine (for example, CCL2, IL-8 and CCL17) secretory capacity; recruit immature myeloid cells from the circulation and aid in their terminal differentiation; and develop/stimulate dendritic cells to prime the adaptive immune response. Activated lymphocytes (for example, GM-CSF-producing T helper cells) can migrate into diseased tissue and the circulation, serving as a source of GM-CSF, thereby aiding in the recruitment and activation of new myeloid cells. GM-CSF levels can also be elevated systemically to induce ‘emergency myelopoiesis’, expanding and mobilizing immature myeloid/progenitor haematopoietic cells in the circulation and bone marrow. These GM-CSF-dependent responses thus heighten the inflammatory response in inflamed or diseased tissue. The broad range of immunological activities of GM-CSF can form part of positive-feedback loops/networks that can initiate and maintain disease-causing hyperactive or chronic immune responses. GM-CSF has also been shown to enhance antimicrobial host defence and lung barrier repair (not shown). Blue arrows mean ‘secretes’, black arrows mean ‘acts on’, dotted arrows indicate movement or differentiation and ‘host cell’ refers to various haematopoietic and non-hematopoietic cell types. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.