Emerging Roles of Lysophosphatidic Acid in Macrophages and Inflammatory Diseases

Abstract

Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that LPA signaling plays a significant role in the physiological function of macrophages and accelerates the development of diseases caused by macrophage dysfunction and inflammation, such as inflammation-related diseases, cancer, atherosclerosis, and fibrosis. In this review, we summarize the roles of LPA in macrophages, analyze numerous macrophage- and inflammation-associated diseases triggered by LPA, and discuss LPA-targeting therapeutic strategies.

Phosphoproteomics Reveals Selective Regulation of Signaling Pathways by Lysophosphatidic Acid Species in Macrophages

“…We were, however, unable to detect significant LPArelated effects in a macropinocytosis assay, which monitored the uptake of dextran by MDMs (see Figure S3). Nonetheless, LPA may influence other forms of phagocytosis that operate through mechanisms distinct from macropinocytosis [17][18][19]52,53].…”

“…The impact of LPA on cancer cell signal transduction, as well as its role in enhancing tumor cell migration and invasion are relatively well-established [4,9,[16][17][18]. This is in marked contrast to its effect on macrophages, which, despite their crucial role in the OC TME, remains surprisingly understudied in a recent review [19]. Limited research has revealed the activation of the Pi3K pathway promoting macrophage survival [20][21][22] and the polarization towards a pro-inflammatory M1 phenotype [23,24].…”

Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis

“… 94 LPAR 1 after activation mediates the physiological effects of LPA including migration, survival, and infiltration of macrophages, activation of inflammasomes, release of proinflammatory mediators, including IL-1 and IL-18, promoting differentiation of mesenchymal cell to myofibroblasts, and collagen excretion. 52 Circulating LPA is increased in SSc patients compared to controls and thus is a natural biomarker and target for treatment of SSc. 94 , 95 Treatment of SSc patients with an LPAR 1 inhibitor resulted in decreases in skin scores and a reduction in LPA-related activation genes, indicating a potentially useful intervention, although more clinical trials are required.…”

“…49 Transforming growth factor-b (TGF-β) is central to the process of fibrosis as well as dysregulation of the immune system toward inflammation. [50][51][52] Injured or stressed cells produce TGF-β that recruits and stimulates macrophages that secrete more TGF-β that then upregulates genes responsible for ECM production and progressive fibrosis. 53,54 Serum cytokeratin 17 (CK17), marginal zone B1 protein (MZB1) and leucine-rich α2-glycoprotein-1 (LRG1) are potential biomarkers for SSc, with CK17 negatively associated with SSc disease severity, with higher CK17 values being protective.…”