Lysophosphatidic Acid Regulates the Differentiation of Th2 Cells and Its Antagonist Suppresses Allergic Airway Inflammation

Abstract

<b><i>Background:</i></b> Lysophosphatidic acid (LPA), a prototypic member of a large family of lysophospholipids, has been recently shown to play a role in immune responses to respiratory diseases. The involvement of LPA in allergic airway inflammation has been reported, but the mechanism remains unclear. <b><i>Object:</i></b> We analyzed the biological activity of LPA in vitro and in vivo and investigated its role in allergic inflammation in mice using an LPA receptor 2 (LPA2) antagonist. <b><i>Methods:</i></b> We used a murine model with acute allergic inflammation, in which mice are sensitized and challenged with house dust mite, and analyzed airway hyperresponsiveness (AHR), pathological findings, Th2 cytokines, and IL-33 in bronchoalveolar lavage fluid (BALF) and lung homogenates. The effect of LPA on Th2 differentiation and cytokine production was examined in vitro using naive CD4<sup>+</sup> T cells isolated from splenocytes. We also investigated in vivo the effects of LPA on intranasal administration in mice. <b><i>Results:</i></b> The LPA2 antagonist suppressed the increase of AHR, the number of total cells, and eosinophils in BALF and lung tissue. It also decreased the production of IL-13 in BALF and IL-33 and CCL2 in the lung. LPA promoted Th2 cell differentiation and IL-13 production by Th2 cells in vitro. Nasal administration of LPA significantly increased the number of total cells and IL-13 in BALF via regulating the production of IL-33 and CCL-2-derived infiltrating macrophages. <b><i>Conclusion:</i></b> These findings suggest that LPA plays an important role in allergic airway inflammation and that the blockade of LPA2 might have therapeutic potential for bronchial asthma.

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

“…Moreover, 2-AG may be converted to arachidonic acid via the monoacylglycerol lipase (MGL) pathway leading to eicosanoid production [ 250 ]. Human leukocytes were found to differentially express CB 1 and CB 2 receptors as well as MGL [ 251 , 252 , 253 ]. Eosinophils, in particular, were shown to express MGL and CB 2 receptor [ 117 , 251 , 253 ] and were found to migrate towards 2-AG [ 254 , 255 ].…”

“…Human leukocytes were found to differentially express CB 1 and CB 2 receptors as well as MGL [ 251 , 252 , 253 ]. Eosinophils, in particular, were shown to express MGL and CB 2 receptor [ 117 , 251 , 253 ] and were found to migrate towards 2-AG [ 254 , 255 ]. Furthermore, the expression of the CB 2 receptor is increased in eosinophils from symptomatic allergic donors and upregulated following ovalbumin challenge in mice, while CB 1 expression was found to be upregulated in tonsils from allergic rhinitis patients [ 117 , 256 , 257 ].…”

“…Furthermore, in vivo application of LPA enhanced infiltration and action of guinea pig eosinophils [ 114 ]. Most studies investigating LPA receptor antagonism in allergic airway diseases focus on targeting LPA 2 , which reportedly suppresses airway hyperresponsiveness and immune cell infiltration in the BALF and lung tissue [ 67 , 251 , 264 , 265 ]. However, a recent study implicates the involvement of LPA receptors 1 and 3 in a neural mechanism involving LPA- induced carotid body activation, leading to acute bronchoconstriction [ 68 ].…”

Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice

“…Lysophosphatidic acid (LPA) is a simple lipid mediator with variable acyl chain lengths. Studies suggest that LPA levels (22:5 and 22:6) are significantly increased in the bronchoalveolar lavage fluid (BALF) of asthmatic patients and mice challenged with segmental allergen and house dust mite (HDM), respectively [ 3 , 4 , 5 ]. Additionally, LPA inhalation induces histamine release and enhances eosinophil and neutrophil infiltration into the lung alveolar spaces in guinea pigs [ 6 , 7 ].…”

“…LPA stimulates the expression of thymic stromal lymphopoietin and CCL20 [ 15 ], and IL-8 production in primary cultured human bronchial epithelial cells by activating p38 MAP kinase and JNK [ 15 , 16 ]. In addition, the expression of LPA 2 was higher than LPA 1 in naïve T cells [ 5 ], and in mouse tracheal epithelial cells LPA 2 mRNA showed the highest expression among LPA 1–4 [ 17 ]. Moreover, LPA 2 deficiency protects against bleomycin-induced lung injury and fibrosis [ 18 ].…”