GM-CSF instigates a dendritic cell–T-cell inflammatory circuit that drives chronic asthma development

Abstract

Background: Steroid-resistant asthma is often characterized by high levels of neutrophils and mixed T H 2/T H 17 immune profiles. Indeed, neutrophils are key drivers of chronic lung inflammation in multiple respiratory diseases. Their numbers correlate strongly with disease severity, and their presence is often associated with exacerbation of chronic lung inflammation.Objective: What factors drive development of neutrophilmediated chronic lung disease remains largely unknown, and we sought to study the role of GM-CSF as a potential regulator in chronic asthma. Methods: Different experimental animal models of chronic asthma were used in combination with alveolar macrophage-From a Molecular Biomedicine,

Alveolar macrophages strictly rely on GM-CSF from alveolar epithelial type 2 cells before and after birth

“…Under conditions of tissue perturbation, ILC-mediated crosstalk via GM-CSF can amplify inflammation through activation of monocytes and eosinophils (Griseri et al, 2015;Song et al, 2015). Although not addressed by our studies, similar cellular interaction modules might also be active in the lung, including in allergic inflammation (Behrens et al, 2015;Nobs et al, 2021). The biological function of constitutive Csf2 expression by pulmonary ILC2s, which we validated on an mRNA and protein level, however, remains unclear.…”

“…Multiple studies suggest that ILC2s shape the neonatal lung environment via their canonical type 2 effector cytokines, IL-5 and IL-13 (Cohen et al, 2018;de Kleer et al, 2016;Nussbaum et al, 2013;Saluzzo et al, 2017;Schneider et al, 2019;Steer et al, 2017). Indeed, the constitutive Csf2 expression by postnatal lung ILC2s is reminiscent of their production of IL-5, by which they regulate eosinophil homeostasis (Nussbaum et al, 2013).…”

“…Multiple studies suggest that ILC2s shape the neonatal lung environment via their canonical type 2 effector cytokines, IL-5 and IL-13 (Cohen et al, 2018;de Kleer et al, 2016;Nussbaum et al, 2013;Saluzzo et al, 2017;Schneider et al, 2019;Steer et al, 2017). Indeed, the constitutive Csf2 expression by postnatal lung ILC2s is reminiscent of their production of IL-5, by which they regulate eosinophil homeostasis (Nussbaum et al, 2013). To determine the relative importance of hematopoietic GM-CSF for AM homeostasis, including GM-CSF derived from ILC2s, we deleted Csf2 expression from the hematopoietic compartment by crossing Csf2 fl mice with Vav1 iCre mice and analyzed P10 neonatal lungs by flow cytometry.…”

“…Our data is in agreement with prior reports, whose findings were based on Csf2 fate-mapping and scRNA-seq analysis (Cohen et al, 2018;Komuczki et al, 2019) Despite the significant homeostatic expression of GM-CSF by various pulmonary immune cells, our studies using Vav1 iCre -mediated Csf2 deletion clearly demonstrate that hematopoietic-derived GM-CSF is dispensable for the postnatal differentiation and the subsequent maintenance of AMs. This finding was unexpected given the high Csf2 expression by ILC2s and the reports suggesting that GM-CSF is included in the ILC2 effector-cytokine repertoire that is induced perinatally (Cohen et al, 2018;de Kleer et al, 2016;Saluzzo et al, 2017;Schneider et al, 2019), and which led to speculation about ILC2 functions in shaping homeostatic myeloid cell compartments beyond the regulation of eosinophils (Nussbaum et al, 2013).…”

Neutrophil extracellular traps and neutrophil-derived mediators as possible biomarkers in bronchial asthma

“…Circulating [81] and BAL levels of CXCL8 [82] are increased in asthmatics. GM-CSF is considered a key orchestrator of neutrophil involvement in chronic airway inflammation [83,84]. VEGF-A, the most important angiogenic factor [85][86][87], is produced by activated human neutrophils [66,88,89].…”