Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

Abstract

Resistin-like molecule a (Relm-a) is one of the most up-regulated gene products in allergen-and parasite-associated Th2 responses. Localized to alternatively activated macrophages, Relm-a was shown to exert an anti-inflammatory effect in parasite-induced Th2 responses, but its role in experimental asthma remains unexplored. Here, we analyzed the cellular source, the IL-4 receptors required to stimulate Relm-a production, and the role of Relm-a after experimental asthma induction by IL-4, IL-13, or multiple experimental regimes, including ovalbumin and Aspergillus fumigatus immunization. We demonstrate that Relm-a was secreted into the airway lumen, dependent on both the IL-13 receptora1 chain and likely the Type I IL-4 receptor, and differentially localized to epithelial cells and myeloid cells, depending on the specific cytokine or aeroallergen trigger. Studies performed with Retnla gene-targeted mice demonstrate that Relm-a was largely redundant in terms of inducing the infiltration of Th2 cytokines, mucus, and inflammatory cells into the lung. These results mirror the dispensable role that other alternatively activated macrophage products (such as arginase 1) have in allergen-induced experimental asthma and contrast with their role in the setting of parasitic infections. Taken together, our findings demonstrate the distinct utilization of IL-4/IL-13 receptors for the induction of Relm-a in the lungs. The differential regulation of Relm-a expression is likely determined by the relative expression levels of IL-4, IL-13, and their corresponding receptors, which are differentially expressed by divergent cells (i.e., epithelial cells and macrophages.) Finally, we identify a largely redundant functional role for Relm-a in acute experimental models of allergen-associated Th2 immune responses.Keywords: resistin-like molecule-a; asthma; IL-4; Asthma is a chronic and complex inflammatory disease of the airways characterized by airflow obstruction, mucus production, airway hyperresponsiveness (AHR), and airway inflammation. It is the most common chronic illness of childhood, affecting up to 20% of children and 7% of adults in Western countries, with a combined prevalence of approximately 300 million people worldwide (1).Asthmatic responses are associated with increased numbers of pulmonary inflammatory cells, including activated T-lymphocytes and eosinophils, which correlate with disease severity (2, 3). T-lymphocytes of the Th2 phenotype are thought to induce asthma through the secretion of an array of cytokines, and in particular, IL-4 and IL-13 (4, 5). These cytokines are produced at elevated concentrations in allergic tissue, and are central regulators of many hallmark features of the disease, such as the production of IgE, Th2 differentiation, eosinophilia, mucus hypersecretion, chemokine induction, and airway hyperresponsiveness (AHR) (6). Notably, IL-13 is considered more of an effector cytokine in the pathogenesis of allergic airway disease compared with IL-4 because AHR and mucus production are predominantly I...

Resistin-Like Molecule α in Allergen-Induced Pulmonary Vascular Remodeling

“…Instead, we found that IL-13, another Th2 cytokine, was up-regulated in OVAchallenged Retnla 2/2 mice ( Figure 5). The increase in IL-13 expression with RELMa depletion is consistent with studies from other investigators (31,32). In a footpad inflammatory model induced by Nocardia cyriacigeorgica (32), IL-13 expression was elevated in the chronic inflammatory phase and inversely correlated with RELMa/ FIZZ1 expression.…”

“…Our current data do not support a role for IL-13 in inducing pulmonary vascular remodeling, and IL-13 is not likely vital to eosinophil recruitment. However, we provide additional evidence that the Th2 response can remain robust after OVA challenge, even when RELMa is deficient, as also reported by Munitz and colleagues (31). They found no difference in inflammatory cell recruitment in Retnla 2/2 mice after IL-13 challenge compared with that in WT mice.…”

IL-4 and IL-13 signaling in allergic airway disease

“…For example, myeloid deficiency in IL-4Ra in mice lead to a reduction in M2 markers (YM-1, Arg1, Relmα) in ovalbumin-induced allergic inflammation, but this reduction resulted in only minor changes in mucus production, eosinophilic inflammation, and collagen deposition [83]. This was mirrored by studies in which a genetic deficiency in either Relmα [84] or Arg-1 [70], had only minor effects on parameters of allergic inflammation. However, one study showed that adoptive transfer of IL-4Rα sufficient macrophages to RAG2−/− mice resulted in an enhancement of allergen-driven lung eosinophil recruitment as compared to the transfer of IL-4Rα-deficient macrophages [82].…”

Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminthHeligmosomoides polygyrus

“…Together with epithelial cells [61], AAMs express high levels of type 2 innate response markers, such as RELMα and Ym1 (where RELM is resistin-like molecule). HES administration was found to potently suppress expression of both of these products ( Fig.…”