Abstract
Hepatic macrophages play an essential role in the granulomatous response to infection with the parasitic helminth Schistosoma mansoni, but the transcriptional changes that underlie this effect are poorly understood. To explore this, we sorted the two previously recognized hepatic macrophage populations (perivascular and Kupffer cells) from naïve and S. mansoni-infected male mice and performed microarray analysis as part of the Immunological Genome Project. The two hepatic macrophage populations exhibited remarkably different genomic profiles. However, this diversity was substantially reduced following infection with S. mansoni, and in fact, both populations demonstrated increases in transcripts of the monocyte lineage, suggesting that both populations may be replenished by monocytes following infection. Pathway analysis showed a profound alteration in global metabolic pathways, including changes to phospholipid and cholesterol metabolism, as well as amino acid biosynthesis and glucagon signaling. These changes suggest a possible mechanism for the previously reported athero-protective effects of S. mansoni infection. Indeed, we find that male ApoE null mice fed a high-fat diet in combination with S. mansoni infection have reduced plaque area and increased glucose tolerance as compared to control mice. Transcript analysis of infected and control high-fat diet fed ApoE−/− mice confirm that ApoC1, Psat1, and Gys1 are all altered by infection, suggesting that altered hepatic macrophage metabolism is associated with S. mansoni- induced protection from hyperlipidemia, atherosclerosis, and glucose intolerance. These results suggest a previously unknown and unreported role of hepatic macrophages in the modulation of whole body lipid and glucose metabolism during infection and provide a template for examining the role of immunomodulation on the long-term metabolism of the host.
Highlights
Macrophages are highly plastic cells with vital functions in host defense and tissue repair and homeostasis [1]
While it is widely accepted that hepatic macrophages play a critical role in the pathology and the survival of S. mansoni infection, the transcriptional changes that accompany the response to S. mansoni antigens are not entirely understood
To explore the transcriptional changes to liver macrophages associated with S. mansoni infection, we first identified hepatic macrophages (CD45+PI−Mertk+CD64+) and sorted F4/80 high (Kupffer cells) and F4/80int populations from the livers of naïve and 10-week old S. mansoni-infected C57BL/6 mice according to Immgen standard protocols [(4, 20), Figures 1A,B]
Summary
Macrophages are highly plastic cells with vital functions in host defense and tissue repair and homeostasis [1] Their distinct functional characteristics depend on their distribution in different anatomical sites as well as the polarization signals from various tissue milieu [2,3,4]. M2 macrophages have previously been shown to play a role in both the defense against some parasitic infections, as well as the transition to chronic helminth infection when immunomodulation and tissue repair is crucial for host survival [8] They are the predominant macrophage in the liver during the Th2 dominated immune response to the helminth Schistosoma mansoni. Knowledge about the transcriptional profile of distinct macrophage subsets during schistosome infection remains limited
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