CXCR Macrophage Facilitates the Resolution of Allergic Lung Inflammation via Interacting CCL26.
Hyung-Geun Moon, Seung-Jae Kim, Ki-Hyun Kim, Young-Mee Kim, Jalees Rehman, Hyun Lee, Yi-Chien Wu, Steve Seung-Young Lee, John W Christman, Steven J Ackerman, Minhyung Kim, Sungyoung You, Gye Young Park
Author Information
Hyung-Geun Moon: Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine.
Seung-Jae Kim: Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine.
Ki-Hyun Kim: Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine.
Young-Mee Kim: Department of Pharmacology.
Jalees Rehman: Department of Pharmacology.
Hyun Lee: Department of Medicinal Chemistry & Pharmacognosy, Center for Biomolecular Sciences.
Yi-Chien Wu: Department of Pharmaceutical Sciences, and. ORCID
Steve Seung-Young Lee: Department of Pharmaceutical Sciences, and. ORCID
John W Christman: Section of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Center, The Ohio State University, Columbus, Ohio.
Steven J Ackerman: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois.
Minhyung Kim: Departments of Surgery, Cedars-Sinai Medical Center, Los Angeles, California; and.
Sungyoung You: Departments of Surgery, Cedars-Sinai Medical Center, Los Angeles, California; and.
Gye Young Park: Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine.
The resolution of inflammation is an active process coordinated by mediators and immune cells to restore tissue homeostasis. However, the mechanisms for resolving eosinophilic allergic lung inflammation triggered by inhaled allergens have not been fully elucidated. Our objectives were to investigate the cellular mechanism of tissue-resident macrophages involved in the resolution process of eosinophilic lung inflammation. For the study, we used the institutional review board-approved protocol for human subsegmental bronchoprovocation with allergen, mouse models for allergic lung inflammation, and novel transgenic mice, including a conditional CCL26 knockout. The samples were analyzed using mass cytometry, single-cell RNA sequencing, and biophysical and immunological analyses. We compared alveolar macrophage (AM) subsets in the BAL before and after allergen provocation. In response to provocation with inhaled allergens, the subsets of AMs are dynamically changed in humans and mice. In the steady state, the AM subset expressing CXCR is a relatively small fraction in bronchoalveolar space and lung tissue but drastically increases after allergen challenges. This subset presents unique patterns of gene expression compared with classical AMs, expressing high C1q family genes. CXCR macrophages are activated by airway epithelial cell-derived CCL26 via a receptor-ligand interaction. The binding of CCL26 to the CXCR receptor induces CXCR macrophages to secrete C1q, subsequently facilitating the clearance of eosinophils. Furthermore, the depletion of CXCR macrophages or CCL26 in airway epithelial cells delays the resolution of allergic lung inflammation displaying prolonged tissue eosinophilia. These findings indicate that the CCL26-CXCR pathway is pivotal in resolving eosinophilic allergic lung inflammation.
