Bronchial asthma (BA) is a heterogeneous chronic inflammatory disease of the airways, characterized by pulmonary inflammation, bronchospasm, shortness of breath, asthma attacks, and coughing [19]. The number of BA patients has drastically increased during the last decades. In some countries the prevalence of this disease reaches 15–18 % [43]. The majority of BA cases (up to 80 %) are atopic and characterized by pronounced allergic symptoms and eosinophilic pulmonary inflammation. This type of asthma is usually developed through Th2-dependent mechanisms and respond to conventional corticosteroid treatment well [1], [22], [46]. Recent data showed that other inflammatory cells – neutrophils could be also involved in asthma pathogenesis [41].

Neutrophils traditionally represent the first line of antibacterial defense due to releasing extracellular traps and antimicrobial factors [31]. Despite the positive antimicrobial role, neutrophils exhibit proinflammatory properties. Excessive penetration of neutrophils into the lungs leads to the tissue damage. Clinical observations showed that increased number of neutrophils in the sputum and exaggerated formation on neutrophil extracellular traps correlated with disease severity in asthma patients [29], [25], [24], [37]. Despite neutrophilic lung inflammation in asthma patients could be induced by environmental factors (respiratory infections, smoking etc.) and comorbid pathologies (obesity) some authors distinguish neutrophilic asthma as separate phenotype [1], [46], [30], [41]. It is noteworthy that severe asthma patients with neutrophilic pulmonary inflammation are often resistant to conventional corticosteroid therapy [30], [26].

Molecular mechanisms of pulmonary neutrophilic inflammation were studied using mouse models of the disease and biopsy obtained from asthma patients. These studies revealed associations of asthma severity and neutrophilic pulmonary inflammation with activation of Th1- [36] and Th17-immune responses [25], [24], [12]. Activated Th1- and Th17-cells release cytokines IFN-γ, IL-17A, IL-17F, IL-8, IL-1ß and TNFα which provide signals for neutrophil migration, maturation and activation [44], [33]. Th17-cytokines (IL-17A, IL-17F, IL-21 and IL-22) play a special role in regulating the neutrophilic inflammation. They promote neutrophil migration by inducing the release of cytokines (IL-6 and IL-8) and chemokines (CXCL1 and CXCL8) from bronchial epithelial cells [33].

Recent studies established another mechanism regulating neutrophil-mediated inflammation. Woytschak et al. [47] established the link between Th2-cytokine IL-4 and inhibition of several neutrophil effector functions and migration. Authors showed that treatment of mice with IL-4 during bacterial skin infections inhibited neutrophil migration and increased bacterial burden and tissue lesions [47]. Additional experiments in a mouse model of systemic infection with Listeria monocytogenes showed that pretreatment of infected mice with IL-4 prevented blood neutrophilia [47]. Similar results were observed in IL-4 treated mice with so called sterile inflammation induced by G-CSF, IL-1b, or monosodium urate crystals. Conversely, these effects of IL-4 were not observed in IL-4Ra-deficient mice or in mice received neutralizing anti-IL-4 monoclonal antibodies [47]. Detailed studies showed that IL-4 has a direct effect on neutrophils. IL-4 interacts with type 2 receptor (consisting of IL-4Ra and IL-13Ra1 chains) on the surface of neutrophils upregulating the expression of chemokine receptor XCR4, which limits the migration of neutrophils. At the same time, IL-4 downregulates another chemokine receptor XCR2 which favors migration of neutrophils toward chemokines CXCL1 and CXCL2. Thus IL-4-mediated signaling dampen migration of neutrophils toward CXCR2-binding chemokines through suppression of XCR2 and activation of XCR4[47].

Despite the emerging data indicating the role of IL-4 in bacterial induced neutrophilia, there are still no studies of IL-4 effects on non-infectious pulmonary neutrophilic inflammation during bronchial asthma. In this study, using previously established mouse model of neutrophilic asthma [40], [39] we showed that systemic administration of IL-4 to mice significantly restrict pulmonary neutrophilic inflammation.