Lysophosphatidic acid signaling in airway epithelium: role in airway inflammation and remodeling

Abstract

Lysophosphatidic acid (LPA), a potent bioactive phospholipid, induces diverse cellular responses, including cell proliferation, migration, and cytokine release. LPA can be generated intracellularly and extracellularly through multiple synthetic pathways by action of various enzymes, such as phospholipase A(1/2) (PLA(1/2)), phospholipase D (PLD), acylglycerol kinase (AGK), and lysophospholipase D (lysoPLD). Metabolism of LPA is regulated by a family of lipid phosphate phosphatases (LPPs). Significant amounts of LPA have been detected in various biological fluids, including serum, saliva, and bronchoalveolar lavage fluid (BALF). The most significant effects of LPA appear to be through activation of the G-protein-coupled receptors (GPCRs), termed LPA(1-6). LPA regulates gene expression through activation of several transcriptional factors, such as nuclear factor-kappaB (NF-kappaB), AP-1, and C/EBPbeta. In addition to GPCRs, cross-talk between LPA receptors and receptor tyrosine kinases (RTKs) partly regulates LPA-induced intracellular signaling and cellular responses. Airway epithelial cells participate in innate immunity through the release of cytokines, chemokines, lipid mediators, other inflammatory mediators and an increase in barrier function in response to a variety of inhaled stimuli. Expression of LPA receptors has been demonstrated in airway epithelial cells. This review summarizes our recent observations of the role of LPA/LPA-Rs in regulation of airway epithelium, especially in relation to the secretion of pro- and anti-inflammatory mediators and regulation of airway barrier function.

Figure 1. Biosynthesis and catabolism of LPA

Activation of PLD generates PA, which is converted to LPA by the action of PLA₁/PLA₂. MAG is converted to LPA by AGK. PC in lipoproteins serves as a substrate of sPLA2 or LCAT, which converts PC to LPC. LPC serves as a substrate of lysoPLD for LPA generation. Levels of LPA are also regulated by LPPs and LPAAT.

Figure 2. LPA signaling in airway epithelial cells

Ligation of LPA to LPA receptors increases intracellular calcium, activates p38 MAPK, PKCs and PLD, resulting in the activation of transcriptional factors and induction of cytokine(s) expression and release; thus regulating innate and adaptive immune responses. LPA induces E-cadherin and c-Met redistribution to cell periphery and regulates airway epithelium integrity.

Figure 3. Signaling pathways of LPA-induced transactivation of EGF-R

Ligation of LPA to its G-protein-coupled receptors induces phosphorylation of EGF-R through PKCδ, Lyn kinase, MMP, and pro-HB-EGF pathway. PLD2 and PKCζ are involved in LPA-induced transactivation of EGF-R; however, the relationship between PLD2 and PKCδ or between PKCζ and Lyn kinase are unclear. Erk1/2 and C/EBPβ are downstream targets of EGF-R transactivation, which regulate cell proliferation and gene expression.

Figure 4. Cross-talk between LPA receptors and RTKs

LPA via its receptors induces tyrosine phosphorylation of EGF-R and PDGF-Rβ (termed as transactivation), and regulates cell proliferation and gene expression. Cross-talk between LPA receptors and c-Met induces serine phosphorylation of c-Met (termed as transinactivation), which enhances airway epithelial barrier function.