Autotaxin Has a Negative Role in Systemic Inflammation

Abstract

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.

Autotaxin in encephalitogenic CD4 T cells as a therapeutic target for multiple sclerosis

“…Of note, LPAR2 is involved in immune cell homing to the spleen during EAE [20], but the contribution of LPAR2 to inflammation seems to vary based on immunological context. Genetic deletion of LPAR2 does not affect LPS‐induced sepsis [14] suggesting that the presence of LPAR2 on T cells is not necessary to fight systemic infection. Interestingly, while global knockout of this receptor in EAE led to worse clinical symptoms, inhibiting LPAR2 therapeutically was clinically beneficial [20].…”

“…Recent studies, however, indicate that increased ATX may have negative effects during both systemic and CNS inflammation, and decreasing ATX in these contexts may be clinically beneficial [13,14]. In a mouse model of LPS-induced neuroinflammation, inhibiting ATX or LPA significantly decreased the presence of proinflammatory markers in both the brain and the periphery [13].…”

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“…Nikitopoulou et al find a negative role of the ATX/LPA axis in systemic inflammation employing the LPS model of experimental sepsis [28]. Genetic deletion of Enpp2, obligatory or induced, increased the survival of mice subjected to this model.…”

A Review of Cyclic Phosphatidic Acid and Other Potential Therapeutic Targets for Treating Osteoarthritis

“…cPA suppresses cancer cell invasion and metastasis by inhibiting ATX and transient activation of low-molecularweight GTPases and RhoA [95]. Additionally, cPA can modulate ATX activity, affecting LPA levels [96] and, consequently, inflammation [97,98]. However, it is important to note that the metabolic stability of cPA can vary depending on factors such as the specific tissue or cell type, presence of enzymes or other molecules that may degrade it, and the local microenvironment.…”