A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma

Abstract

Complement component 5 (C5) has been described as either promoting or protecting against airway hyperresponsiveness (AHR) in experimental allergic asthma, suggesting pleomorphic effects of C5. Here we report that local pharmacological targeting of the C5a receptor (C5aR) prior to initial allergen sensitization in murine models of inhalation tolerance or allergic asthma resulted in either induction or marked enhancement of Th2-polarized immune responses, airway inflammation, and AHR. Importantly, C5aR-deficient mice exhibited a similar, increased allergic phenotype. Pulmonary allergen exposure in C5aR-targeted mice resulted in increased sensitization and accumulation of CD4 + CD69 + T cells associated with a marked increase in pulmonary myeloid, but not plasmacytoid, DC numbers. Pulmonary DCs from C5aR-targeted mice produced large amounts of CC chemokine ligand 17 (CCL17) and CCL22 ex vivo, suggesting a negative impact of C5aR signaling on pulmonary homing of Th2 cells. In contrast, C5aR targeting in sensitized mice led to suppressed airway inflammation and AHR but was still associated with enhanced production of Th2 effector cytokines. These data suggest a dual role for C5a in allergic asthma, i.e., protection from the development of maladaptive type 2 immune responses during allergen sensitization at the DC/T cell interface but enhancement of airway inflammation and AHR in an established inflammatory environment.

Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling

“…Later, Kim et al (12) observed that mice treated with C5aR antagonist have impaired CD8 T cell response to influenza type A virus, suggesting that C5a-C5aR interaction plays an important role in generation of Ag specific T cell responses. In contrast to in the virus model, Kohl et al (34) found that in the asthma model, blocking C5aR resulted in induction of marked enhancement of Th2 immune response, suggesting that C5a-C5aR interaction down-regulates Th2 immune response which is thought to play a critical role in asthma pathogenesis. Recent studies reported that when APC and T cell were encountered, C5a interaction with C5aR on both cells can provide costimulatory and survival signals to naive CD4 T cells, thus up-regulate Ag-specific T cell responses (14).…”

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…In the lung, PDCs are among the earliest inflammatory cells to enter the bronchoalveolar space following influenza A virus infection [81], and support the recruitment of CXCR3 + and CCR5 + effector T cells through the local secretion of CXCL10 and CCL5 [82]. A protective role for C5a in allergic asthma has been linked to a shift in the MDC/PDCs ratio toward PDCs, with an accompanying decrease in CCL17 production [83]. Furthermore, PDCs depletion exacerbates respiratory syncytial virus lung immunopathology [84].…”

Complement Receptors in Inflammation

“…Similar results are observed when C5aR is blocked prior to initial pulmonary HDM challenge. Together, this data suggests that the presence of C5a in the airways at the time of initial allergen encounter serves to prevent the development of Th2-mediated immune response (Kohl et al, 2006). Protection against allergic sensitization by C5aR activation is a complex process involving alterations in the function of APCs, in particular dendritic cells.…”

“…CD4 + T cells from mice challenged with HDM allergen in presence of an anti-C5aR monoclonal antibody produce higher levels of Th2 cytokines in co-culture with mDCs, but not with pDCs. Importantly, in the same setting, pDCs suppress the mDC-induced production of Th2 cytokines (Kohl et al, 2006). Furthermore, exposure to HDM leads to an increased number of mDCs, whereas the number of pDCs remains unaffected.…”