CCL4 Functions as a Biomarker of Type 2 Airway Inflammation

Abstract

Eosinophilic airway inflammatory disease is associated with bronchial asthma, with eosinophilic chronic rhinosinusitis (ECRS) typical of refractory type 2 airway inflammation. CCL4 produced at local inflammatory sites is involved in them via the accumulation and activation of type 2 inflammatory cells, including eosinophils. The detailed mechanism of CCL4 production remains unclear, and also the possibility it could function as a biomarker of type 2 airway inflammation remains unresolved. In this study, we evaluated CCL4 mRNA expression and production via the TSLP receptor (TSLPR) and toll-like receptors (TLRs) or proteinase-activated receptor-2 (PAR2) in BEAS-2B bronchial epithelial cells co-incubated with purified eosinophils or eosinophil peroxidase (EPX). We examined serum chemokine (CCL4, CCL11, CCL26, and CCL17) and total IgE serum levels, fractionated exhaled nitrogen oxide (FENO), and CCL4 expression in nasal polyps in patients with severe ECRS and asthma. CCL4 was induced by TSLP under eosinophilic inflammation. Furthermore, CCL4 was released via TLR3 signaling, which was enhanced by TSLP. CCL4 was mainly located in nasal polyp epithelial cells, while serum CCL4 levels were reduced after dupilumab treatment. Serum CCL4 levels were positively correlated with FENO, serum IgE, and CCL17 levels. Thus, CCL4 released from epithelial cells via the innate immune system during type 2 airway inflammation may function as a useful biomarker for the condition.

Human bocavirus 1 coinfection is associated with decreased cytokine expression in the rhinovirus‐induced first wheezing episode in children

“…IL‐1b and TNFa are pro‐inflammatory cytokines, known for their crucial role in host defense in response to infections and injuries, in the induction of proinflammatory proteins, as well as in the promotion of differentiation of Th17 cells 31,32 . MIP‐1b and RANTES are generally classified as type 2 associated chemokines, known for recruitment of eosinophils, for example, in the airways 33,34 . However, in recent studies, the latter have been suggested to have more pleiotropic capabilities 35 .…”

“…31,32 MIP-1b and RANTES are generally classified as type 2 associated chemokines, known for recruitment of eosinophils, for example, in the airways. 33,34 However, in recent studies, the latter have been suggested to have more pleiotropic…”

“… 31 , 32 MIP‐1b and RANTES are generally classified as type 2 associated chemokines, known for recruitment of eosinophils, for example, in the airways. 33 , 34 However, in recent studies, the latter have been suggested to have more pleiotropic capabilities. 35 Moreover, in RV‐affected subjects, RANTES has been associated with bronchial smooth muscle cell chemotaxis, thereby contributing to possible airway remodeling.…”

Role of macrophages in pulmonary arterial hypertension

“…Studies have shown that CCR4 shows a more obvious M2 activation, as demonstrated by the elevated representation of the archetypal M2 markers ARG1 and FIZZ1 (132)(133)(134). Chemokine C-X-C motif ligand 4 (CXCL4/PF-4), a platelet-derived chemokine (135,136), has been shown to prevent monocyte apoptosis and promote macrophage differentiation in vitro (137). In addition, CCR5 is expressed on pulmonary vascular walls and macrophages, and upregulated in PAH (59).…”

Olfactomedin 4 as a circulating biomarker for asthma

“…Diagnostic biological molecules for the neutrophilic inflammatory type of bronchial asthma include increase in sputum neutrophils, blood neutrophils, expression of YLK-40 protein, and hydrogen sulfide in sputum and serum ( 15 , 16 ). Thymic stromal lymphopoietin (TSLP), microbiome, neutrophil extracellular traps, and the activation of the nucleotide-binding oligomerization domain-like receptor family and pyrin domain-containing 3 pathways, are phenotypes of neutrophilic asthma.…”