Abstract
BackgroundComplement factor C5 can either aggravate or attenuate the T-helper type 2 (TH2) immune response and airway hyperresponsiveness (AHR) in murine models of allergic asthma. The effect of C5 during the effector phase of allergen-induced asthma is ill-defined.ObjectivesWe aimed to determine the effect of C5 blockade during the effector phase on the pulmonary TH2 response and AHR in a house dust mite (HDM) driven murine asthma model.MethodsBALB/c mice were sensitized and challenged repeatedly with HDM via the airways to induce allergic lung inflammation. Sensitized mice received twice weekly injections with a blocking anti-C5 or control antibody 24 h before the first challenge.ResultsHDM challenge in sensitized mice resulted in elevated C5a levels in bronchoalveolar lavage fluid. Anti-C5 administered to sensitized mice prior to the first HDM challenge prevented this rise in C5a, but did not influence the influx of eosinophils or neutrophils. While anti-C5 did not impact the recruitment of CD4 T cells upon HDM challenge, it reduced the proportion of TH2 cells recruited to the airways, attenuated IL-4 release by regional lymph nodes restimulated with HDM ex vivo and mitigated the plasma IgE response. Anti-C5 did not affect innate lymphoid cell (ILC) proliferation or group 2 ILC (ILC2) differentiation. Anti-C5 attenuated HDM induced AHR in the absence of an effect on lung histopathology, mucus production or vascular leak.ConclusionsGeneration of C5a during the effector phase of HDM induced allergic lung inflammation contributes to TH2 cell differentiation and AHR without impacting ILC2 cells.
Highlights
Complement factor C5 can either aggravate or attenuate the T-helper type 2 (TH2) immune response and airway hyperresponsiveness (AHR) in murine models of allergic asthma
Generation of C5a during the effector phase of house dust mite (HDM) induced allergic lung inflammation contributes to TH2 cell differentiation and AHR without impacting Proliferation or group 2 ILC (ILC2) cells
Repeated HDM challenge triggered an influx of leukocytes into bronchoalveolar lavage (BAL) fluid (Fig. 1b),which was the result of recruitment of eosinophils (Fig. 1c) and neutrophils (Fig. 1d)
Summary
Complement factor C5 can either aggravate or attenuate the T-helper type 2 (TH2) immune response and airway hyperresponsiveness (AHR) in murine models of allergic asthma. Activation of the complement system can occur through three pathways (i.e., the classical, lectin and alternative pathways), which lead to downstream proteolytic cleavage of C3 and C5, resulting in the release of the anaphylatoxins C3a and C5a [4, 5]. Genetic deletion or pharmacological blockade of C5 or the C5a receptor (C5aR) resulted in a strongly enhanced allergic phenotype [13, 14]. C5a/C5aR signaling can induce IL-12 production in antigen presenting cells and potentiates skewing toward TH1 responses [16]. Eliminating C5a/ C5aR signaling after the sensitization phase reduced allergic lung inflammation [17] and AHR [18, 19]. The underlying mechanisms for this C5a mediated proallergic effect in an established inflammation environment is not well understood
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