Facilitating Resolution of Allergic Lung Inflammation

Inflammation is important for healing, but if it persists unchecked, it can lead to tissue damage and organ dysfunction. Recent research shows that stopping inflammation requires an active cellular process in addition to suppressing pro-inflammatory signals. In allergic asthma, eosinophils are the main inflammatory cells in the lung, and their apoptosis must be eliminated by tissue macrophages to restore homeostasis. CX3CR1 is a receptor expressed in myeloid cells, and recent studies suggest that CX3CR1+ tissue-derived macrophages have a unique function in maintaining or restoring tissue homeostasis. While CX3CL1 is the known ligand for CX3CR1, recent research suggests that CCL26, produced by airway epithelial cells, may also play a key role in the resolution of eosinophilic lung inflammation by CX3CR1+ macrophages.

Today, we look at the results of a recently published study that aimed to investigate the cellular mechanism of tissue-resident macrophages involved in the resolution process of eosinophilic pneumonia. The study was approved by the Institutional Review Board, and an Investigational New Drug was approved by the FDA for bronchoscopic administration of allergens to study volunteers. Subjects with therapy level 1 asthma were recruited and screened for inclusion and exclusion criteria. Bronchoalveolar lavage (BAL) was performed before and after subsegmental bronchoprovocation with the identified allergen (SBP-AG). The BAL cells obtained were analyzed by mass cytometry using metal-conjugated antibodies. Data were analyzed using viSNE and FlowSOM software. Detailed information on the methods can be found in the publication.

Study reveals role of CX3CR1+ macrophages and CCL26 in regulating eosinophil populations during allergic lung inflammation

The study examines the regulation of eosinophil populations during allergic inflammation in human and mouse models. The investigators find that upon allergen exposure, CX3CR1+ macrophages and eosinophil receptor double-positive cells increase in bronchoalveolar lavage (BAL) from humans and mice. Depletion of CX3CR1 delays clearance of tissue eosinophilia in allergic lung inflammation. The study also shows that CX3CR1+ cells and receptor function of CX3CR1 regulate eosinophil populations in a steady state. Furthermore, the data suggest that CX3CR1 plays a critical role in maintaining the balance between eosinophils and macrophages in allergic inflammation.

In addition, the results show that C1q is highly expressed by CX3CR1+ alveolar macrophages (AMs) and that selective depletion of C1q in CX3CR1+ cells delayed the clearance of eosinophilia in BAL fluid in the mouse asthma model. The study also found that CCL26 binds to CX3CR1 with a 100-fold higher binding affinity than CX3CL1. Although CCR3 is the known receptor for CCL26, its expression in CX3CR1+ AMs in the lung is minimal, suggesting a marginal role of CCL26 by CCR3 in the lung. CCL26 is mainly produced by airway epithelial cells and is enhanced by allergen exposure. This study found that depletion of CCL26 from AEC in the late phase of allergic inflammation allows persistent eosinophilia in the lung, suggesting a possible role of CCL26 in the late phase of allergic inflammation.

The authors conclude:

At a glance

That pretty much sums it up:

• CX3CR1+ macrophages and eosinophil receptor double-positive cells increase in bronchoalveolar lavage (BAL) from humans and mice upon allergen exposure.

• CX3CR1 plays a critical role in maintaining the balance between eosinophils and macrophages in allergic inflammation.

• CCL26 binds to CX3CR1 with a 100-fold higher binding affinity than CX3CL1, suggesting a pivotal role of the CCL26-CX3CR1 pathway in resolving eosinophilic allergic lung inflammation.

• Depletion of CCL26 from airway epithelial cells in the late phase of allergic inflammation allows persistent eosinophilia in the lung.