Schistosoma mansoni Infection-Induced Transcriptional Changes in Hepatic Macrophage Metabolism Correlate With an Athero-Protective Phenotype

<p> Hepatic macrophages play an essential role in the granulomatous response to infection</p> <p>with the parasitic helminth Schistosoma mansoni , but the transcriptional changes</p> <p>that underlie this effect are poorly understood. To explore this, we sorted the two</p> <p>previously recognized hepatic macrophage populations (perivascular and Kupffer cells)</p> <p>from naïve and S. mansoni -infected male mice and performed microarray analysis as</p> <p>part of the Immunological Genome Project. The two hepatic macrophage populations</p> <p>exhibited remarkably different genomic profiles. However, this diversity was substantially</p> <p>reduced following infection with S. mansoni , and in fact, both populations demonstrated</p> <p>increases in transcripts of the monocyte lineage, suggesting that both populations</p> <p>may be replenished by monocytes following infection. Pathway analysis showed a</p> <p>profound alteration in global metabolic pathways, including changes to phospholipid</p> <p>and cholesterol metabolism, as well as amino acid biosynthesis and glucagon</p> <p>signaling. These changes suggest a possible mechanism for the previously reported</p> <p>athero-protective effects of S. mansoni infection. Indeed, we find that male ApoE null</p> <p>mice fed a high-fat diet in combination with S. mansoni infection have reduced plaque</p> <p>area and increased glucose tolerance as compared to control mice. Transcript analysis</p> <p>of infected and control high-fat diet fed ApoE−/− mice confirm that ApoC1 , Psat1 ,</p> <p>and Gys1 are all altered by infection, suggesting that altered hepatic macrophage</p> <p>metabolism is associated with S. mansoni - induced protection from hyperlipidemia,</p> <p>atherosclerosis, and glucose intolerance. These results suggest a previously unknown</p> <p>and unreported role of hepatic macrophages in the modulation of whole body lipid and</p> <p>glucose metabolism during infection and provide a template for examining the role of immunomodulation on the long-term metabolism of the host.</p>