Granulocyte-macrophage colony-stimulating factor: an immunotarget for sepsis and COVID-19

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF), which belongs to the colony-stimulating factor (CSF) superfamily and was originally identified as a hemopoietic growth factor, is mainly produced by lymphocytes and innate lymphoid cells. Nonhematopoietic cell populations such as fibroblasts, endothelial cells, and epithelial cells may also secrete GM-CSF in response to an activating stimulus. Currently, GM-CSF is considered to play a smaller role in homeostatic myelopoiesis in a steady state because GM-CSF-gene-deficient mice exhibit steady-state hematopoiesis and a virtually normal lifespan of granulocytes and monocytes [1]. During the course of inflammation, systemic GM-CSF dramatically increases monocyte and neutrophil production from the bone marrow and plays an important role in the expansion and differentiation of myeloid cells [2]. Moreover, GM-CSF is deemed essential for resistance to local infection and normal pulmonary physiology. GM-CSF deficiency results in pulmonary alveolar proteinosis characterized by the failure to clear surfactant from the lungs due to a shortage of macrophages induced by GM-CSF. GM-CSF is rarely detectable in the peripheral blood of healthy individuals and is expressed basally in nonsterile tissues such as the lung, gut, and skin. During inflammation, GM-CSF is principally produced by T helper (Th) cells and acts as a communication conduit between myeloid cells and tissue-invading lymphocytes. In an experimental autoimmune encephalomyelitis mouse model, the interleukin (IL)-7-STAT5 axis promotes the generation of GMCSF/IL-3-producing Th cells, which are designated Th-GMs, exhibit a distinct transcriptional profile, and represent a novel subset of Th cells [3]. In another experimental autoimmune encephalomyelitis mouse model, it was reported that GM-CSF is critical for the proinflammatory functions of Th17 cells; GM-CSF blockade, but not IL-17 depletion, may efficiently inhibit tissue inflammation [4]. Therefore, GM-CSF is considered an important proinflammatory cytokine and not only a supplementary medication for patients with neutropenia secondary to chemotherapy-induced myelosuppression. Sepsis is a life-threatening medical condition caused by the entry of various microorganisms into the human bloodstream that triggers an uncontrolled inflammatory reaction [5]. The systemic inflammatory response syndrome/compensatory antiinflammatory response state model or persistent inflammationimmunosuppression catabolism syndrome model are used to depict the immune status of sepsis patients. An increased number of peripheral GM-CSF-producing CD4+ T cells were shown to serve as a marker of severity in patients with sepsis [6]. However, exogenous GM-CSF administration improved the survival of patients with sepsis by enhancing phagocytosis by neutrophils and monocytes and increasing reactive oxygen species generation. Therefore, a better stratification of the immune status with a tailored approach is essential for the treatment of patients with sepsis. The expression of monocytic human leukocyte antigen DR (mHLA-DR) in fewer than 30% of cells, reduction in the lipopolysaccharide (LPS)-induced TNF-α level to <200 pg/mL in whole blood, and an absolute lymphocyte count <1000 cells/mm are significant factors for immunoparalysis [7]. GM-CSF stimulates the production of neutrophils and monocytes by the bone marrow and maintains the activation and survival of monocytes. GM-CSF restored cytokine secretion in monocytes from sepsis patients by reducing apoptosis and increased CD71 and HLA-DR expression on monocytes upon synergistic coordination with LPS in vitro [8]. Many clinical studies have found that GM-CSF treatment has a potential benefit for patients with sepsis. In a prospective, randomized, open-label clinical study, GM-CSF treatment facilitated the recovery of the TNF-α response and prevented nosocomial infection in children with nonneutropenic, nontransplant, and severe multiple organ dysfunction syndrome [9]. Strong evidence has shown that mHLA-DR and plasma IL-6 levels are closely related to the outcome of recombinant human GM-CSF administration, and sepsis patients treated with GM-CSF have a shorter length of stay in the hospital or intensive care units [10]. In another randomized phase II trial, although GM-CSFtreated patients with sepsis showed improvement in PaO2/FiO2 and increased peripheral blood neutrophil counts, GM-CSF therapy did not reverse acute respiratory distress syndrome and had no effect on 30-day survival [11]. As GM-CSF application might lead to different results in severe sepsis at different stages, we suggest that biomarker-guided, individualized precision therapies based on the immune status may work in a well-defined patient population (Fig. 1). Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 and has become a global pandemic. As a proinflammatory cytokine and myelopoietic growth factor, GM-CSF plays an essential role in mediating alveolar macrophage homeostasis and lung inflammation in COVID-19. Under homeostatic conditions, a low GM-CSF level is critical for the development and long-term maintenance of alveolar macrophages. For this reason, an inhaled GM-CSF formulation is being assessed for patients with COVID-19-related acute hypoxic respiratory failure (NCT04326920). In the later stages of COVID-19, increased GM-CSF levels may serve as a link between T cell-mediated acute pulmonary inflammation and a self-amplifying cytokine loop, which leads to the activation of