Immunomodulatory Mediators from Pollen Enhance the Migratory Capacity of Dendritic Cells and License Them for Th2 Attraction

Abstract

The immune response of atopic individuals against allergens is characterized by increased levels of Th2 cytokines and chemokines. However, the way in which the cytokine/chemokine profile is matched to the type of invading allergen, and why these profiles sometimes derail and lead to disease, is not well understood. We recently demonstrated that pollen modulates dendritic cell (DC) function in a way that results in an enhanced capacity to initiate Th2 responses in vitro. Here, we examined the effects of aqueous birch pollen extracts (Bet.-APE) on chemokine receptor expression and chemokine production by human monocyte-derived DCs. Bet.-APE strongly induced expression and function of CXCR4 and reduced CCR1 and CCR5 expression on immature DCs. In addition, DC treatment with Bet.-APE significantly reduced LPS-induced production of CXCL10/IP-10, CCL5/RANTES; induced CCL22/macrophage-derived chemokine; and did not significantly change release of CCL17/thymus and activation-regulated chemokine. At a functional level, Bet.-APE increased the capacity of LPS-stimulated DCs to attract Th2 cells, whereas the capacity to recruit Th1 cells was reduced. Bet.-APE significantly and dose-dependently enhanced intracellular cAMP, suggesting that water-soluble factors from pollen grains bind a Gαs-protein-coupled receptor. E1-Phytoprostanes were identified to be one player in the Th2-polarizing potential of aqueous pollen extracts. In summary, our results demonstrate that pollen itself releases regulatory mediators which generate a Th2-promoting micromilieu with preferential recruitment of Th2 cells to the site of pollen exposure.

Pollen-Derived E1-Phytoprostanes Signal via PPAR-γ and NF-κB-Dependent Mechanisms

“…1A). Bet.-APE stimulation lead to a strong, dose-dependent cAMP induction, which, as observed before, was 3-to 4-fold higher than that elicited by PGE 2 (9). The cAMP induction elicited by Bet.-APE was attenuated in the presence of the EP2 and EP4 antagonists (Fig.…”

“…Although the observed strong cAMP inducing activity of Bet.-APE likely has to be ascribed to substance(s) different from PPE 1 , it remains to be determined whether other PALM(s) or protein(s) mediate this effect. We could recently show that Bet.-APE, much like PGE 2 , enhance the migration of LPS-stimulated DC toward the chemokines CCL19, CCL21, and CXCL-12, an effect that was abrogated in the presence of an adenylyl cyclase inhibitor (9). Moreover, incubation of DC with LPS plus Bet.-APE, but not with PPE 1 , lead to enhanced secretion of the T H 2-attracting chemokine CCL17 (9).…”

“…Among these are a number of bioactive lipids (5), the so-called pollen-associated lipid mediators (PALMs). 3 Hitherto existing data point to two main groups of PALMs: First, the immunostimulatory PALMs activating and stimulating cells of the innate immune system such as neutrophils and eosinophils (6,7) and, second, the immunomodulatory PALMs acting on cytokine and chemokine production of human dendritic cells (DC) skewing the immune systems toward a Type-2 dominated proallergenic immune response (8,9). The finding that PALMs activate and modulate cells of the immune system added a new, as yet unappreciated aspect to the concept of pollen as mere vehicles of allergens (10).…”

Cupressaceae Pollen Grains Modulate Dendritic Cell Response and Exhibit IgE-Inducing Adjuvant Activity In Vivo

“…Lipid fractions from birch and grass pollen extracts induce chemotaxis and the activation of neutrophils (14) and eosinophils (15). Pollen extracts of birch, hazel, lilac, maple, and mugwort and birch pollen phytoprostanes inhibit LPS-induced IL-12 production (16) and birch pollen extract, and phytoprostanes enhance migratory and Th2-attracting capacities (17) in dendritic cells (DCs).…”

Die Achse Umwelt‐Erreger‐Wirt bei übertragbaren und nicht übertragbaren Krankheiten: Jüngste Fortschritte in der experimentellen und klinischen Forschung

“…Andere PALMs, die eine strukturelle Ähnlichkeit mit den Prostaglandinen aus Säugetierzellen aufweisen, modulieren dendritische Zellen, so dass diese eine Th2-gewichtete T-Zell Antwort induzieren und die Differenzierung naiver T-Zellen zu Th-1-Zellen hemmen [11][12][13]. Darüber hinaus produzieren dendritische Zellen unter dem Einfluss der PALMs Chemokine, die vermehrt Th2-Zellen rekrutieren [14]. Auch in Mausmodellen konnte die Th1-hemmende Wirkung der PALMs und eine Mastzellaktivierung durch nicht-allergene Substanzen in Pollen gezeigt werden [15,16].…”