GM-CSF produced by the airway epithelium is required for sensitization to cockroach allergen

Abstract

Airway epithelial cells are among the first to encounter inhaled allergens and can initiate allergic responses by producing pro-Th2 innate cytokines. In this study, we investigated the role of epithelial-derived cytokines in sensitization to a clinically relevant allergen, cockroach allergen (CRA). Among the epithelial-derived cytokines, GM-CSF played a central role in the initiation of Th2 allergic responses to CRA. We show that initial exposure to CRA directly activated airway epithelial cells through a TLR4-MyD88-dependent pathway and MyD88 signaling in epithelial cells induced upregulation of GM-CSF during sensitization. Epithelial-derived GM-CSF was required for allergic sensitization and selectively restored Th2 responses in the absence of MyD88. Thus, we demonstrate that epithelial-derived GM-CSF is a critical early signal during allergic sensitization to CRA.

The atopic march: current insights into skin barrier dysfunction and epithelial cell‐derived cytokines

“…193 GM-CSF was also found to be required in a model of cockroach antigen (CRA)-induced airway inflammation. 194 In this CRA-induced allergy model, TSLP and IL-25 were not required, and lack of IL-33 only moderately affected CRA-induced inflammation.…”

“…In a model of intranasal sensitization and challenge with HDM, blockade of either IL‐33 or GM‐CSF abolished HDM‐induced disease, whereas TSLP was important only when high doses of HDM were administered . GM‐CSF was also found to be required in a model of cockroach antigen (CRA)‐induced airway inflammation . In this CRA‐induced allergy model, TSLP and IL‐25 were not required, and lack of IL‐33 only moderately affected CRA‐induced inflammation.…”

Interplay between barrier epithelial cells and dendritic cells in allergic sensitization through the lung and the skin

“…As a consequence, DC maturation was impaired and the typical Th2‐mediated airway inflammation, which occurred upon airway HDM challenges, was completely prevented . The central role of TLR4 in the initiation of Th2 immunity to environmental allergens has, since, been shown by several groups, and the specific requirement of TLR4 on lung ECs in Th2 responses has recently been confirmed in a study using transgenic mice that conditionally lacked TLR4 in ECs . How exactly allergens can trigger TLR4 signaling is currently unknown.…”

GM-CSF in inflammation

“…Cellular sources of GM-CSF and GM-CSF networks Both hemopoietic (e.g., lymphocytes and innate lymphoid cells [ILCs]) and nonhemopoietic cell populations (e.g., fibroblast, endothelial, and epithelial populations; see below) can produce GM-CSF, although they usually require an activating stimulus (Hamilton, 2008;Campbell et al, 2011;Rauch et al, 2012;Willart et al, 2012;Becher et al, 2016;Pearson et al, 2016;Anzai et al, 2017;Sheih et al, 2017;Chen et al, 2018;Hu et al, 2019). Consistent with this requirement, in the steady state, GM-CSF circulates at low levels and is usually expressed basally in nonsterile tissues such as lung, gut, and skin (Metcalf and Nicola, 1995;Hamilton and Achuthan, 2013).…”

“…In contrast, in line with resident tissue cells being potential GM-CSF sources (Hamilton, 1993a(Hamilton, ,b, 2008, GM-CSF production by fibroblast-like synoviocytes helps initiate experimental autoimmune arthritis (Hirota et al, 2018), and its expression by cardiac fibroblasts has been implicated in the pathogenesis of Kawasaki disease (Stock et al, 2016) as well as in experimental autoimmune myocarditis and myocardial infarction (Chen et al, 2018). Epithelial cells have been proposed to produce GM-CSF in response to allergenic stimuli as a critical early signal during allergic sensitization (Willart et al, 2012;Sheih et al, 2017).…”