**2.4 Chemokine markers**

Eotaxin, as a ESO chemokine, can attract EOS to the site of allergic inflammation by stimulating CCR3. Eotaxin played a role in the early stage of Th2 lymphocyte recruitment [65], and the concentration of airway eotaxin was related to the sensitivity of asthmatic airway [66]. A study has demonstrated that there was a direct relationship between asthma diagnosis and eotaxin, and the levels of plasma eotaxin were negatively correlated with pulmonary function [66].

CCR2 was expressed in monocytes and T lymphocytes [67]. CCR2 mediated release of monocyte precursors leads to the increase of lung dendritic cells (DC) in allergic airway inflammation [68]. A study showed that monocytes may modulate the inflammatory response in asthma [69]. In a mouse asthma model, CCL2/CCR2 dependent recruitment of Th17 cells to the lung promoted airway inflammation [70]. In a monkey asthma model, Neutralization of CCR2 reduced bronchial hyperreactivity and weakened the accumulation of macrophages and eosinophils in BALF [71]. Therefore, the elevated CCR2 was a diagnostic biomarker for asthma.

CCR3 was mainly expressed on EOS, and can also be detected on basophils and T cells [67]. CCR3 showed sequence homology in many species, including humans, mice and guinea pigs. Its expression was limited to cells involved in allergic inflammation [72]. MicroRNA30a3p (miR30a3p)can inhibit CCR3 signaling pathway, reduce the secretion of sIgE against ovalbumin (OVA), eotaxin, IL5 and IL4 [73]. The expression of CCR3 on the surface of PBMCs was positively correlated with severity of asthma [74]. Inhibition of CCR3 blocks eosinophil recruitment into the blood, lungs and airways and prevents AHR in a mouse asthma model [75].

CCR5 was expressed in T lymphocytes and macrophages [67]. The increased CCR5 lead to EOS accumulation and airway remodeling in asthma patients [76]. Compared with healthy subjects, the expression of CCR5 in peripheral blood lymphocytes increased in asthma patients, and inhibition of CCR5 was a feasible method for blocking AHR [77, 78].

Thymus and activationregulated chemokine (TARC) was produced by DC, endothelial cells, keratinocytes, bronchial epithelial cells and fibroblasts [79]. As chemokine related T2 inflammation, TARC contributed to the activation of EOS and MC driven by Th2 [80]. A series of studies concluded that the TARC concentration of asthma children increased in plasma [81], and after treatment of systemic corticosteroid (CS), the concentration decreased. In addition, the levels of TARC were negatively correlated with indicator of lung function such as peak expiratory flow rates in asthma patients [82].

Monocyte chemotactic protein4 (MCP4) was a potential chemical attractant not only for EOS, but also for monocytes, lymphocytes and basophils [83]. It have been

confirmed that MCP4 can induce histamine release and activation of the EOS [74]. Plasma MCP4 was higher in patients with acute asthma than in those with chronic stable asthma [83], which implied that MCP4 was correlated with exacerbation of asthma.
