Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions

TY - JOUR

T1 - Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions

AU - Beattie, Lynette

AU - Sawtell, Amy Kathleen

AU - Mann, Jason

AU - Frame, Teija C.M.

AU - Teal, Bianca

AU - de Labastida Rivera, Fabian

AU - Brown, Najmeeyah

AU - Walwyn-Brown, Katherine

AU - Moore, John Warren James

AU - MacDonald, Alexander James

AU - Lim, Eng-Kiat

AU - Dalton, Jane Elise

AU - Engwerda, Christian R.

AU - MacDonald, Kelli P.

AU - Kaye, Paul

N1 - © 2016 European Association for the Study of the Liver. Published by Elsevier B.V.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Abstract:Background and aims: Kupffer cells (KCs), the resident tissue macrophages of theliver, play a crucial role in the clearance of pathogens and other particulate materials that reach the systemic circulation. Recent studies have identified KCs as a yolk sac-derived resident macrophage population that is replenished independently of monocytes in the steady state. Although it is now established that following local tissue injury, bone-marrow derived monocytes may infiltrate the tissue and differentiate into macrophages, the extent to which newly differentiated macrophages functionally resemble the KCs they have replaced has not been extensively studied.Methods and results: Here we show using intravital microscopy, morphometricanalysis and gene expression profiling that bone marrow derived “KCs” accumulating as a result of genotoxic injury resemble, but are not identical to their yolk-sac (YS) counterparts. An ion homeostasis gene signature, including genes associated with scavenger receptor function and extracellular matrix deposition, allows discrimination between these two KC populations. Reflecting the differential expression of scavenger receptors, YS-derived KCs were more effective at accumulating Ac-LDL, whereas surprisingly they were poorer than BM-derived KCs when assessed for uptake of a range of bacterial pathogens. The two KC populations were almost indistinguishable in regard to i) response to LPS challenge, ii) phagocytosis of effete RBCs and iii) their ability to contain infection and direct granuloma formation against Leishmania donovani, a KC-tropic intracellular parasite.Conclusions: BM-derived KCs differentiate locally to resemble YS-derived KC inmost but not all respects, with implications for models of infectious diseases, liverinjury and bone marrow transplantation. In addition, the gene signature we describe adds to the tools available for distinguishing KC subpopulations based on their ontology.

AB - Abstract:Background and aims: Kupffer cells (KCs), the resident tissue macrophages of theliver, play a crucial role in the clearance of pathogens and other particulate materials that reach the systemic circulation. Recent studies have identified KCs as a yolk sac-derived resident macrophage population that is replenished independently of monocytes in the steady state. Although it is now established that following local tissue injury, bone-marrow derived monocytes may infiltrate the tissue and differentiate into macrophages, the extent to which newly differentiated macrophages functionally resemble the KCs they have replaced has not been extensively studied.Methods and results: Here we show using intravital microscopy, morphometricanalysis and gene expression profiling that bone marrow derived “KCs” accumulating as a result of genotoxic injury resemble, but are not identical to their yolk-sac (YS) counterparts. An ion homeostasis gene signature, including genes associated with scavenger receptor function and extracellular matrix deposition, allows discrimination between these two KC populations. Reflecting the differential expression of scavenger receptors, YS-derived KCs were more effective at accumulating Ac-LDL, whereas surprisingly they were poorer than BM-derived KCs when assessed for uptake of a range of bacterial pathogens. The two KC populations were almost indistinguishable in regard to i) response to LPS challenge, ii) phagocytosis of effete RBCs and iii) their ability to contain infection and direct granuloma formation against Leishmania donovani, a KC-tropic intracellular parasite.Conclusions: BM-derived KCs differentiate locally to resemble YS-derived KC inmost but not all respects, with implications for models of infectious diseases, liverinjury and bone marrow transplantation. In addition, the gene signature we describe adds to the tools available for distinguishing KC subpopulations based on their ontology.

UR - http://www.scopus.com/inward/record.url?scp=84979729483&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2016.05.037

DO - 10.1016/j.jhep.2016.05.037

M3 - Article

SN - 0168-8278

VL - 65

SP - 758

EP - 768

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 4

ER -