Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization

Abstract

Airway epithelial cells (AECs) secrete innate immune cytokines that regulate adaptive immune effector cells. In allergen-sensitized humans and mice, the airway and alveolar microenvironment is enriched with colony stimulating factor-1 (CSF1) in response to allergen exposure. In this study we found that AEC-derived CSF1 had a critical role in the production of allergen reactive-IgE production. Furthermore, spatiotemporally secreted CSF1 regulated the recruitment of alveolar dendritic cells (DCs) and enhanced the migration of conventional DC2s (cDC2s) to the draining lymph node in an interferon regulatory factor 4 (IRF4)-dependent manner. CSF1 selectively upregulated the expression of the chemokine receptor CCR7 on the CSF1R cDC2, but not the cDC1, population in response to allergen stimuli. Our data describe the functional specification of CSF1-dependent DC subsets that link the innate and adaptive immune responses in T helper 2 (Th2) cell-mediated allergic lung inflammation.

Colony‐stimulating factor 1 and its receptor are new potential therapeutic targets for allergic asthma

“…Among DC subsets, cDC2 have been shown to play an essential role in antigen presentation in allergic lung inflammation . Our data show a marked surge of cDC2 in BAL fluid in the DRA asthma model . However, it is not fully understood how alveolar cDC2 are regulated in allergic inflammation.…”

“…Next, mice were subjected to the chronic DRA model and the cDC2s were rapidly increased over the course of the chronic DRA model, but cDC1s were delayed until week 6. Because CSF1R + cDC2 play critical role in allergen sensitization, we further analyzed CSF1R + cDCs in the BAL fluids. Chronic DRA exposure induced an earlier and higher increase in CSF1R + cDC2 than that of CSF1R + cDC1 (Figure B).…”

“…Selective CSF1R inhibitors have been used in continuing clinical trials for cancer treatment with minimal adverse effects . GW2580, a CSF1R inhibitor, showed excellent binding affinity to human CSF1R recombinant protein . Simulation protein structure modeling indicated that GW2580 interacts with two critical intracellular tyrosine residues (Y546 and Y665) of the kinase domain of CSF1R (Figure ).…”

“…C57BL/6, Scgb1a1‐CreERT (stock# 016225), Irf4 fl/fl (stock# 009 380), and MAFIA (stock #005070) mice were purchased from Jackson Laboratory (Bar Harbor, ME). Scgb1a1‐creERT;Csf1 fl/fl and Csf1r‐creERT;Irf4 fl/fl were generated as described previously . Mice were bred in a specific pathogen‐free facility maintained by the University of Illinois at Chicago.…”

“…Here, we show the effectiveness of blocking CSF1 and its receptor (CSF1R) in asthma treatment. To this end, we utilized GW2580, a selective CSF1R inhibitor, which previously showed excellent pharmacokinetics . To ensure scientific rigor, we employed a robust chronic mouse model of allergic lung and airway inflammation with naturally occurring allergens.…”