Allergen‐induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34⁺ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation

Abstract

SUMMARYThere is increasing evidence that primitive progenitors migrate from the bone marrow (BM) via the peripheral circulation to tissue sites where they undergo in situ differentiation to provide a continued source of effector cells, such as eosinophils, during an allergic in¯ammatory response. To study mechanisms of progenitor cell mobilization in allergic reactions, we investigated uctuations in the expression of the eotaxin receptor, CC chemokine receptor 3 (CCR3), on CD34 cells from stable asthmatics following allergen (i.e. antigen) challenge. BM aspirates were taken from seven early responder (ER) and 10 dual responder (DR) asthmatics who, following antigen challenge developed only an early bronchoconstrictor response and an early and latebronchoconstrictor response, respectively. Expression of CCR3 was detected on primitive (CD34 cells) and eosinophil-lineage committed progenitors (CD34 interleukin-5 receptor alpha-subunit cells) by¯ow cytometry and con®rmed by co-localization of CCR3 messenger RNA to CD34 immunopositive cells using in situ hybridization. When preantigen levels were compared to 24-hr postantigen levels, signi®cant increases in BM CD34 CCR3 cells were detected in DR, who also developed a signi®cant sputum and blood eosinophilia and increased methacholine airway responsiveness. In contrast, a signi®cant attenuation of BM CD34 CCR3 cells was observed in ER. In a dose-dependent manner eotaxin, but not interleukin (IL)-5, stimulated CD34 progenitor cell migration in vitro. This migrational response to eotaxin was abrogated by anti-CCR3 monoclonal antibody and primed by preincubation with IL-5. We propose that¯uctuations in CCR3 expression on human BM CD34 cells may facilitate chemokine-mediated progenitor cell mobilization to the peripheral circulation and the resultant development of pulmonary eosinophilia, a cardinal feature of asthma.

Up-Regulation and Activation of Eosinophil Integrins in Blood and Airway after Segmental Lung Antigen Challenge

“…Such activation contrasts with the model for the recruitment of leukocytes (16), including eosinophils (20), in which integrin activation is assumed to occur locally and concurrently with rolling and tethering on endothelium. Interestingly, bone marrow-derived progenitor cells or circulating eosinophils of asthmatics have been shown to be activated upon Ag challenge also as measured by the up-regulation of IL-5 receptor ␣ and CCR3, the activation of CD32, and greater responsiveness to chemoattractants (42,(81)(82)(83). Further, eosinophils from allergic asthmatics have been shown to have a greater capacity to adhere to and transmigrate through endothelium than eosinophils from normal donors (51,84).…”

IL-21 Administration into the Nostril Alleviates Murine Allergic Rhinitis

“…The eotaxin family members are CC chemokines that exert a chemoattractive activity for eosinophils, while eotaxins also facilitate the differentiation of eosinophils as well as the rapid mobilization of eosinophils and their progenitors from the bone marrow (54,55). Eotaxins have been shown to play pivotal roles in recruiting eosinophils to the nasal mucosa in allergic rhinitis, where IL-4 provokes nasal fibroblasts to secrete eotaxins (36, 56 -58), although there have been some contradictory reports on the roles of eotaxins in airway inflammation and allergy (1,2,59,60).…”

Anti-interleukin-5 therapy in severe asthma

“…Thus, in order to obtain the most clinical response in eosinophilic asthma, a systemic approach to anti-IL-5 therapy may be important. Eotaxin is an accompanying chemokine with a dose-dependent capacity to stimulate migration of eosinophil CD34 + progenitor cells [10]. Some observations also suggest that the eotaxin/CCR3 interaction, independently of IL-5, may be involved in the survival and function of eosinophils in the airways and in clinical symptoms [11].…”