Invading macrophages play a major role in the liver progenitor cell response to chronic liver injury.
OBJECTIVE
Although a strong association between liver progenitor cells (LPCs) and inflammation exists in many chronic liver diseases, the exact role of the immune system in LPC-mediated hepatic regeneration remains unclear. A number of pro-inflammatory factors were identified in cytokine knockout mice in which the LPC response was attenuated but neither the mechanism nor the producing cells are known.


METHODS
To identify the critical immune cells and cytokines required in the LPC response, we compared two diet-induced models of liver injury with two recently established transgenic models of immune-mediated hepatitis.


RESULTS
Despite severe inflammation being observed in all models, the generation of LPCs was highly dependent on the cause and kinetics of liver damage. The LPC response was associated with an increase of macrophages and CD8(+) T cells but not natural killer cells. T cell-deficient mice were able to mount a LPC response, albeit delayed, suggesting that T cells are not essential. Mice mounting an LPC response showed elevated numbers of Kupffer cells and invading CX(3)CR1(high)CCR2(high) macrophages secreting persistent high levels of tumour necrosis factor alpha (TNFalpha), a major cytokine involved in the LPC response.


CONCLUSIONS
Liver macrophages are an important determinant of LPC expansion during liver regeneration in models of diet- and immune-mediated liver injury. Invading macrophages in particular provide pro-mitogenic cytokines such as TNFalpha that underpin the process. LPC themselves are a source of chemokines (CCL2, CX(3)CL1) that attract infiltrating macrophages.
Viebahn
Cornelia S
CS
School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Australia. connyviebahn@web.de
Benseler
Volker
V
Holz
Lauren E
LE
Elsegood
Caryn L
CL
Vo
Michelle
M
Bertolino
Patrick
P
Ganss
Ruth
R
Yeoh
George C T
GC
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D002908:Chronic Disease; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000473:pathology*; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008115:Liver Regeneration / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D013234:Stem Cells / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; C515335:Ccr2 protein, mouse; C471885:Cx3cr1 protein, mouse; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha