Circulating, but not local lung, IL-5 is required for the development of antigen-induced airways eosinophilia.

Abstract

IL-5 is induced locally in the lung and systemically in the circulation during allergic airways eosinophilic inflammation both in humans and experimental animals. However, the precise role of local and systemic IL-5 in the development of allergic airways eosinophilia remains to be elucidated. In our current study, we demonstrate that compared with their IL-5 ϩրϩ counterparts, IL-5 Ϫ / Ϫ mice lacked an IL-5 response both in the lung and peripheral blood, yet they released similar amounts of IL-4, eotaxin, and MIP-1 ␣ in the lung after ovalbumin (OVA) sensitization and challenge. At cellular levels, these mice failed to develop peripheral blood and airways eosinophilia while the responses of lymphocytes, neutrophils, and macrophages remained similar to those in IL-5 ϩրϩ mice. To dissect the relative role of local and systemic IL-5 in this model, we constructed a gene transfer vector expressing murine IL-5. Intramuscular IL-5 gene transfer to OVA-sensitized IL-5 Ϫ / Ϫ mice led to raised levels of IL-5 compartmentalized to the circulation and completely reconstituted airways eosinophilia upon OVA challenge, which was associated with reconstitution of eosinophilia in the bone marrow and peripheral blood. Significant airways eosinophilia was observed for at least 7 d in these mice. In contrast, intranasal IL-5 gene transfer, when rendered to give rise to a significant but compartmentalized level of transgene protein IL-5 in the lung, was unable to reconstitute airways eosinophilia in OVA-sensitized IL-5 Ϫ / Ϫ mice upon OVA-challenge, which was associated with a lack of eosinophilic responses in bone marrow and peripheral blood. Our findings thus provide unequivocal evidence that circulating but not local lung IL-5 is critically required for the development of allergic airways eosinophilia. These findings also provide the rationale for developing strategies to target circulating IL-5 and/or its receptors in bone marrow to effectively control asthmatic airways eosinophilia. ( J.

Eosinophilopoiesis in A Murine Model of Allergic Airway Eosinophilia: Involvement of Bone Marrow IL-5 and IL-5 Receptor α

“…This inhibitory effect is parallel with a strong inhibition of the bone marrow eosinophilia. The importance of the circulating IL-5 for airway eosinophilia is in line with one of our previous studies, showing that airway eosinophilia can be induced in sensitized IL-5 knockout mice by systemic reconstitution with IL-5, but not by local lung reconstitution (26). Thus, systemic IL-5 seems to be important for the induction of airway eosinophilia, and this effect is likely to involve stimulation of eosinophilopoiesis.…”

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization

“…Eosinophilia despite reduced airway IL-5 may be due to the lack of reduction in LN-derived IL-5 because peripheral, but not airway-specific, expression of IL-5 has been demonstrated to be required for the induction of airway eosinophilia (16). A similar phenotype was seen with postsensitization treatment with Ag-SP, in which airway Th2 cytokines were inhibited but Ag-specific IgE and airway eosinophilia were exacerbated (4).…”

IL-5 Up-Regulates Cysteinyl Leukotriene 1 Receptor Expression in HL-60 Cells Differentiated into Eosinophils

“…Intravenous IL-5 dramatically enhances the local accumulation of eosinophils induced by intradermal eotaxin or LTB 4 in guinea pigs (47). Circulating, rather than local, pulmonary IL-5 is required for the development of Ag-induced airways eosinophilia, possibly through its action at the level of the bone marrow (48). Since undifferentiated HL-60 cells are arrested at the promyelocytic stage of myelopoiesis, it is interesting to observe that CysLT 1 R expression is already found in myeloid precursor cells, although additional studies with primary bone marrow-derived cells will be necessary to confirm this possibility.…”