Acute myocardial infarction (AMI) initiates pathological inflammation which aggravates tissue damage and causes heart failure. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), promotes inflammation and the development of atherosclerosis. The role of ATX/LPA signaling nexus in cardiac inflammation and resulting adverse cardiac remodeling is poorly understood. We assessed autotaxin activity and LPA levels in relation to cardiac and systemic inflammation in AMI patients and C57BL/6 (WT) mice. Human and murine peripheral blood and cardiac tissue samples showed elevated levels of ATX activity, LPA, and inflammatory cells following AMI and there was strong correlation between LPA levels and circulating inflammatory cells. In a gain of function model, lipid phosphate phosphatase-3 (LPP3) specific inducible knock out (Mx1-Plpp3Δ) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3fl/fl); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3Δ mice, cardiac functional recovery was reduced with corresponding increases in adverse cardiac remodeling and scar size (as assessed by echocardiography and Masson's Trichrome staining). To examine the effect of ATX/LPA nexus inhibition, we treated WT mice with the specific pharmacological inhibitor, PF8380, twice a day for 7 days post AMI. Inhibition of the ATX/LPA signaling nexus resulted in significant reduction in post-AMI inflammatory response, leading to favorable cardiac functional recovery, reduced scar size and enhanced angiogenesis. ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury. Schematic summarizing the role of autotaxin/lysophosphatidic acid signaling in post-AMI inflammation and cardiac dysfunction. Damage associated molecular pattern molecules released from dying cardiomyocytes and cardiac fibroblasts initiate an inflammatory cascade resulting in the activation of Autotaxin/lysophosphatidic acid signaling; which in turn augments local and systemic inflammation through the release of inflammatory cytokines and chemokines. Systemically, activation of bone marrow progenitors results in increased production of inflammatory cells. Locally, increased chemoattractants such as MCP-1 results in increased infiltration of inflammatory cells to the damaged myocardium. Collectively, these events result in prolonged and exacerbated inflammatory response and impaired cardiac functional recovery Display omitted •LPA-ATX signaling nexus modulated post-myocardial infarction inflammation.•Pharmacological inhibition of ATX/LPA signaling attenuates cardiac and systemic inflammation post-AMI.•ATX inhibition post-AMI enhances cardiac recovery, reduces adverse remodeling and scar size.