The early immune response is mediated mainly by inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor-α (TNF-α). It has been reported that IL-1β and TNF-α are present in the epithelial environment within hours of infection (19,20). IL-1β and TNF-α then induce the expression of chemokines in epithelial cells (11). It has previously been demonstrated that TNF-α stimulates the expression of C-C motif chemokine ligands CCL2, CCL4, CCL5, CCL11 and CCL20. Furthermore, airway epithelial cells release CCL5 and CCL20 upon stimulation by IL-1β (18). IL-1β can also induce the expression of CCL3 and CCL4 in airway epithelial cells by activating nuclear factor (NF)-κB. In addition, NF-κB also activates transcription of the gene encoding CCL2 as its promoter contains an NF-κB binding site (21,22).

Several other inflammatory cytokines can induce the expression of certain chemokines. Previous studies have revealed that TNF-α in combination with IL-4 or IL-13 upregulates the expression and secretion of CCL17 in epithelial cells (23,24). It has also been indicated that CCL11 and CCL20 are produced following IL-4 or IL-13 stimulation (25). Furthermore, it has been demonstrated that clusterin induces the production of CCL20 by regulating the oxidative stress environment in airway epithelial cells from mice studies (26). Previous studies have demonstrated that microRNA-34a, 15-lipoxygenase and histamine are important regulators for CCL22 in airway epithelial cells (27–29).

In addition, airway epithelial cells produce chemokines in response to immunological environmental factors including microbial and viral stimuli (11). Viral or bacterial infection induces the secretion of high levels of CCL2, CCL5 and CCL20 by airway epithelial cells (30). Furthermore, infection by viruses increases CCL5 expression in different types of cells. For example, respiratory syncytial virus infection results in enhanced expression of CCL5 in human nasal mucosa and gland epithelial cells, and infection by influenza virus induces CCL5 expression in human bronchial tissues and nasal polyp epithelial cells (31). In addition, Der p allergens from house dust mites induce CCL17 expression in bronchial epithelial cells which appears to be mediated by a disintegrin and metalloproteinase-dependent phosphorylation of epidermal growth factor receptor and subsequent activation of mitogen-activated protein kinase (MAPK) and NF-κB (32).

It has been demonstrated that IL-17 promotes the expression of CXCL1 and CXCL5 in bronchial epithelial cells and that IL-17 potentially promotes CXCL1 expression mainly through the extracellular regulated protein kinases (ERK) or MAPK pathway (33). At the same time, different cytokines stimulate CXCL8 secretion under the control of different signaling pathways, including NF-κB, ERK, c-Jun N-terminal kinase (JNK) and MAPK pathways (34). Additionally, Janus kinase (JAK) and the synergistic effect of TNF-α and interferon-γ can induce CXCL10 expression in airway epithelial cells (35). On this basis, these associated signaling molecules have also been used as potential targets of anti-inflammatory treatment. It has been identified that the inhibition of JAK pathway in the airway epithelium may provide an alternative anti-inflammatory approach to glucocorticosteroid-resistant diseases in vitro (36). It has also been observed that the long-acting β2 agonists downregulate poly I:C-induced CXCL10 expression in bronchial epithelial cells via the β2 adrenoreceptor-cyclic adenosine monophosphate and JNK pathways in vitro (37).

Various cytokines including thymic stromal lymphopoietin (TSLP) and IL-33 secreted by airway epithelial cells have previously been identified to possess very strong recruitment effects on inflammatory cells. They are also classified as chemokines not belonging to the traditional four classic chemokine families (38,39).

Previous studies have revealed that TNF-α and IL-1β can induce the expression of IL-33 (40). Park et al (41) verified that TNF-α stimulates IL-33 expression in primary nasal epithelial cells and A549 cells via the NF-κB, ERK and MAPK pathways in vitro. Furthermore, IL-33 has been reported to induce the production of TSLP in bronchial epithelial cells following activation by antigens (42). Respiratory syncytial virus infection can also rapidly transfer stress signals through the JNK and MAPK pathways via direct stimulation of epithelial cells to upregulate expression of TSLP (43).

Recruitment of Th2 cells and the subsequent production of Th2-type cytokines form the main characteristics of asthma airway inflammation (44). DCs are sentinels of the adaptive immune system as they can induce the differentiation of Th2 cells. The key role of DCs in asthma pathogenesis has been a subject of attention for more than 15 years (1).

In the pathogenesis of asthma, the secretion of CCL20, IL-33 and TSLP is substantially increased following stress by allergens and other pathogenic substances. C-C chemokine receptor CCR6, IL-33R and TSLPR (corresponding receptors for CCL20, IL-33 and TSLP respectively) are expressed on immature DCs (iDCs). By binding with these receptors, CCL20, IL-33 and TSLP activate iDCs and promote their maturation (26,42). DCs then migrate to the T cell zone in mediastinal lymph nodes, where they activate T cells via antigen presentation and co-stimulation. Furthermore, TSLP upregulates the expression of surface co-stimulatory molecules, including CD40, CD80 and CD86 on DCs. Under the influence of secreted cytokines and membrane-expressed molecules including OX40 L, Jagged1, IL-6 and leukotrienes C4, activated inflammatory DCs interact with naive CD4⁺T cells and induce the differentiation of Th2, Th17 and follicular helper T cells (45,46). CCR3 and CCR4 surface receptors of Th2 cells directly bind to chemokines secreted by epithelial cells. CCR4 interacts with CCL17/CCL22, and CCR3 interacts with CCL13 (27). Animal studies have indicated that targeted blocking of CCR4/CCR3 receptors can significantly reduce the eosinophil ratio in the bronchoalveolar lavage fluid of asthmatic model mice (47). Following prompting by the actions of these chemokines, Th2 cells infiltrate into the site of inflammation where they secrete cytokines including IL-4, IL-5, IL-13 and TNF-α (Fig. 1). These cytokines in turn cause enhanced airway mucus secretion and airway epithelial structure destruction, further provoking airway inflammation and AHR (48,49). IL-4 induces B cell activation and the secretion of IgE; IL-13 causes goblet cell metaplasia, AHR and increases the expression of adhesion molecules on vascular endothelial cells (44,50). Furthermore, IL-4 and IL-13 can also promote the secretion of CCL17 by airway epithelial cells, and IL-13 can promote the secretion of CCL22 (23). These chemokines, which result from cascade amplification, further induce the aggregation of Th2 cell infiltration. The specific enhanced expression of TSLP in airway epithelial cells results in initial CD4⁺T lymphocyte proliferation and Th2 cell differentiation (38). Conversely, targeting TSLP with short hairpin RNA or antibodies, alleviates airway inflammation and decreases epithelial CCL17 in a murine model of asthma (51,52).

In addition to activated DCs and Th2 cells, eosinophils also act as key effector cells in the airway inflammation of asthma. The invasion of eosinophils in the airway is closely associated with the severity of asthma (53). Eosinophils initially form in the bone marrow and differentiate from progenitor cells. By rolling adhesion and exudation, eosinophils interact with endothelial cells. Eosinophils are activated to release granule-associated proteins, which cause airway epithelial injury, smooth muscle contraction, inflammatory cell infiltration and AHR (54). In this process, CCL5 and CCL11 function as potent eosinophil chemoattractants by binding to CCR3 (Fig. 2). CCL11 also induces eosinophil chemotaxis via the activation of ERK and MAPK pathways (55). CXCL8 and CXCL10 can also bind to CXCR2 and CXCR3, respectively, on eosinophils to induce the recruitment of eosinophils. Following the recruitment to the airway inflammation area, eosinophils release various inflammatory mediators and toxic proteins (including eosinophil cationic protein, myelin basic protein, palmitic acid and IL-5 which further aggravate airway inflammation. Eosinophils also produce protein particles to cause tissue damage (56) and respiratory burst (57,58).

Although asthma is classically associated with eosinophilia and Th2 cytokines, certain asthma patients exhibit a neutrophil-predominant phenotype without evident Th2 cytokines. CXCL8 and CXCL10 possess a strong chemotactic effect on neutrophils (Fig. 2). Takaku et al (58) identified that CXCL10 and CXCL8 are elevated in asthma phenotypes with increasing eosinophils and neutrophils in airways. In addition, CXCL8, CXCL1 and CXCL5 can bind to CXCR2 (a specific surface receptor on neutrophils), which can activate neutrophils and attract them to inflammation sites. These chemokines also promote expression of adhesion molecules, (including CD11a, -b, -c and CD18) and cause cell deformation, eosinophil degranulation and respiratory burst (59–61). In addition, TNF-α, leukotriene B4 and other inflammatory mediators produced by activated neutrophils further exacerbate airway inflammation, leading to airway submucosal edema and goblet cell metaplasia (62).

An increasing number of studies have demonstrated that ILC2 s contribute to the initiation and maintenance of the adaptive Th2 immune response (63,64). By binding to IL-33R on ILC2 cells, IL-33 promotes production of IL-5 and IL-13 by ILC2 (Fig. 2). IL-13 secreted by ILC2 cells can bind to IL-13R on macrophages, which further induce the activation of macrophages (65). In addition, early eosinophilia in the lung is driven by IL-5 that also supports the development of eosinophils in the bone marrow. Consequently, ILC2 cells contribute to Th2 cell-mediated lung inflammation in the pathogenesis of asthma (66).

Monocytes express specific high-affinity receptors for CCL2, CXCL10, CCR2 and CXCR3 (9). Macrophage recruitment occurs via a chemotactic gradient of monocyte selective chemokines. Following activation and recruitment, monocytes release superoxide anions and lysozymes (67). At the same time, surface-specific adhesion molecules CD11c and CD11b are expressed on monocytes, which are involved in the regulation of airway inflammation. In addition, the increased expression of integrin β2 and α4 is accompanied by upregulated IL-1 and IL-6 (68). Interactions between mucosal epithelial cells and macrophages are pivotal to allergic lung inflammation. Increased expression of CCL2 has been reported in asthmatic airway epithelial cells, blocking the CCL2-CCR2 axis and attenuating the asthma phenotype in other animal models of asthma (69).