C5aR1 activation in mice controls inflammatory eosinophil recruitment and functions in allergic asthma

Abstract

Background Pulmonary eosinophils comprise at least two distinct populations of resident eosinophils (rEOS) and inflammatory eosinophils (iEOS), the latter recruited in response to pulmonary inflammation. Here, we determined the impact of complement activation on rEOS and iEOS trafficking and function in two models of pulmonary inflammation. Methods BALB/c wild‐type and C5ar1−/− mice were exposed to different allergens or IL‐33. Eosinophil populations in the airways, lung, or mediastinal lymph nodes (mLN) were characterized by FACS or immunohistochemistry. rEOS and iEOS functions were determined in vivo and in vitro. Results HDM and IL‐33 exposure induced a strong accumulation of iEOS but not rEOS in the airways, lungs, and mLNs. rEOS and iEOS expressed C3/C5 and C5aR1, which were significantly higher in iEOS. Initial pulmonary trafficking of iEOS was markedly reduced in C5ar1−/− mice and associated with less IL‐5 production from ILC2 cells. Functionally, adoptively transferred pulmonary iEOS from WT but not from C5ar1−/− mice‐induced airway hyperresponsiveness (AHR), which was associated with significantly reduced C5ar1−/− iEOS degranulation. Pulmonary iEOS but not rEOS were frequently associated with T cells in lung tissue. After HDM or IL‐33 exposure, iEOS but not rEOS were found in mLNs, which were significantly reduced in C5ar1−/− mice. C5ar1−/− iEOS expressed less costimulatory molecules, associated with a decreased potency to drive antigen‐specific T cell proliferation and differentiation into memory T cells. Conclusions We uncovered novel roles for C5aR1 in iEOS trafficking and activation, which affects key aspects of allergic inflammation such as AHR, ILC2, and T cell activation.

Complement‐mediated immune mechanisms in allergy

“…Finally, C5aR1 is instrumental for iEOS recruitment into the draining pulmonary lymph nodes (dLN) and their potency to drive T-cell proliferation and differentiation into effector memory T cells [50]. During the effector phase, C5aR1 activation fosters the proallergic environment through iEOS and cDC activation triggering AHR, Th2 immunity, and airway inflammation [6,33,50]. This image was created with the help of Biorender.com.…”

“…Further, C5aR1 controls the potency of cDC2 cells to drive Th cell proliferation and Th2 differentiation as well as the pDC/cDC2 ratio in the lung [33]. Finally, C5aR1 is instrumental for iEOS recruitment into the draining pulmonary lymph nodes (dLN) and their potency to drive T-cell proliferation and differentiation into effector memory T cells [50]. During the effector phase, C5aR1 activation fosters the proallergic environment through iEOS and cDC activation triggering AHR, Th2 immunity, and airway inflammation [6,33,50].…”

“…The role of C5a/C5aR1 axis activation is more complex (middle panel). During allergen sensitization, C5aR1 controls ILC2-mediated initial recruitment of iEOS through IL-5 [50]. Further, C5aR1 controls the potency of cDC2 cells to drive Th cell proliferation and Th2 differentiation as well as the pDC/cDC2 ratio in the lung [33].…”

“…Finally, C5aR1 was critical for the potency of draining pulmonary lymph node‐derived iEOS to drive allergen‐induced T‐cell proliferation and differentiation (Fig. 1) [50]. However, a direct role of the C5a/C5aR1 axis in Th2 or Th17 differentiation is unclear.…”