Abstract Rationale Airflow obstruction unresponsive to β2 adrenergic receptor (β2AR) agonists is a key feature of infant respiratory syncytial virus (RSV) bronchiolitis. The underlying mechanisms remain poorly understood, and effective treatment is lacking. Objectives To investigate whether and how infant RSV infection affects β2AR signaling in airway smooth muscle cells (ASMCs). Methods We established complementary human and mouse models of RSV infection using infant (0–18 months) precision-cut lung slices (PCLSs), neonatal epithelial air-liquid interface (ALI) culture, and mouse pups to assess β2AR-mediated ASMC relaxation. Cytokine profiling was performed using conditioned medium (CM) from RSV-infected neonatal ALI culture. Infant ASMCs treated with CM were subjected to bulk RNA sequencing and β2AR expression and function assays. Findings were validated with nasopharyngeal aspirates (NPA) from infants with severe bronchiolitis. Measurements and main results RSV selectively targeted infant bronchial epithelium, inducing cytokine secretion that impaired β2AR-mediated ASMC relaxation. CXCL11 was the most upregulated epithelial cytokine and signaled to infant ASMCs through ACKR3, a β-Arrestin-poised receptor that interacted with β2AR to promote its phosphorylation, internalization, and degradation. Using mouse strains with genetic variation in Cxcl11, along with ACKR3 blockade and CXCL11 rescue assays, we demonstrated that CXCL11-ACKR3 signaling was both necessary and sufficient for β2AR dysfunction. Moreover, blockade of CXCL11 or ACKR3 restored β2AR responsiveness in infant PCLSs exposed to RSV or NPA from severe RSV bronchiolitis. Conclusions Infant RSV bronchiolitis exploits CXCL11-ACKR3 signaling to desensitize β2AR in ASMCs. Targeting this pathway may improve β2AR agonist efficacy in severe RSV bronchiolitis.
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Caiqi Zhao
Alice E Taliento
Elise Belkin
American Journal of Respiratory and Critical Care Medicine
Massachusetts General Hospital
Boston University
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Zhao et al. (Wed,) studied this question.
www.synapsesocial.com/papers/699fe33695ddcd3a253e6d80 — DOI: https://doi.org/10.1093/ajrccm/aamag087