Ceramides and sphingosine-1-phosphate mediate the distinct effects of M1/M2-macrophage infusion on liver recovery after hepatectomy

Abstract

Post-hepatectomy liver dysfunction is a life-threatening morbidity that lacks efficient therapy. Bioactive lipids involved in macrophage polarization crucially regulate tissue injury and regeneration. Herein, we investigate the key bioactive lipids that mediate the cytotherapeutic potential of polarized-macrophage for post-hepatectomy liver dysfunction. Untargeted lipidomics identified elevation of ceramide (CER) metabolites as signature lipid species relevant to M1/M2 polarization in mouse bone-marrow-derived-macrophages (BMDMs). M1 BMDMs expressed a CER-generation-metabolic pattern, leading to elevation of CER; M2 BMDMs expressed a CER-breakdown-metabolic pattern, resulting in upregulation of sphingosine-1-phosphate (S1P). After infusing M1- or M2-polarized BMDMs into the mouse liver after hepatectomy, we found that M1-BMDM infusion increased M1 polarization and CER accumulation, resulting in exaggeration of hepatocyte apoptosis and liver dysfunction. Conversely, M2-BMDM infusion enhanced M2 polarization and S1P generation, leading to alleviation of liver dysfunction with improved hepatocyte proliferation. Treatment of exogenous CER and S1P or inhibition CER and S1P synthesis by siRNA targeting relevant enzymes further revealed that CER induced apoptosis while S1P promoted proliferation in post-hepatectomy primary hepatocytes. In conclusion, CER and S1P are uncovered as critical lipid mediators for M1- and M2-polarized BMDMs to promote injury and regeneration in the liver after hepatectomy, respectively. Notably, the upregulation of hepatic S1P induced by M2-BMDM infusion may have therapeutic potential for post-hepatectomy liver dysfunction.

C‐C motif chemokine ligand 5 confines liver regeneration by down‐regulating reparative macrophage‐derived hepatocyte growth factor in a forkhead box O 3a–dependent manner

“…[ 29 ] In addition, LR and recovery of liver function are accelerated significantly when reparative bone‐marrow–derived macrophages (BMDMs) are infused into hepatectomized mice. [ 13 ] However, the underlying mechanism in which reparative macrophages affected LR were not clearly shown. Our study showed that increased proportion of reparative Ly6C lo and subsequent HGF production may contribute to an advanced proliferation peak after major hepatectomy.…”

“…[ 11 , 12 ] Recent studies have shown that the cytokines produced by polarized macrophages may regulate liver repair and regeneration after hepatectomy. [ 13 , 14 ] However, the specific roles of Ly6C lo and Ly6C hi macrophages and their secreted cytokines in LR remain unclear.…”

Magnetic resonance imaging of tumor-associated-macrophages (TAMs) with a nanoparticle contrast agent

“…The results of these studies illustrated that an established primary culture model for macrophage subtypes (BMDM) [45][46][47][48] exhibited inconsistent expression of the M2 surface marker, SR-A. [6][7][8]46 There was no signicant difference in uptake of SDIO, which is targeted to SR-A, between polarized phenotypes in BMDMs.…”

Role of Sphingolipids in Multiple Myeloma Progression, Drug Resistance, and Their Potential as Therapeutic Targets

“…Recently, untargeted lipidomic analysis conducted in mouse BM-derived macrophages (BMDM) identified signature lipid species relevant to the M1/M2 polarization. While M1 BMDMs expressed a ceramide-generation metabolic pattern, leading to elevation of ceramide, M2 BMDMs expressed a ceramide-breakdown-metabolic pattern, resulting in upregulation of S1P ( 112 ).…”