Page 78 - Read Online

Page 6 of 15 Song et al. Hepatoma Res 2020;6:27 I http://dx.doi.org/10.20517/2394-5079.2020.05

HBV suppresses pattern recognition receptors (PRRs) sensing or downstream interferon (IFN) response
[78]
in hepatocytes but activate macrophages to secrete cytokines at high titer . Furthermore, HBc protein is
detected within macrophages in liver tissues from HBV-infected patients. Macrophages exposed to HBV or
HBV-producing cells are prone to secrete more IL-10, which subsequently impairs lymphocyte activation,
[76]
but less pro-inflammatory cytokines such as IL-6 and IL-1β with property of inhibition on HBV infection .
Accordingly, HBV drives macrophages to be suppressive immune cells. In offspring with horizontal
transmission of HBV, HBeAg induces up-regulation of checkpoint molecular PD-L1 on macrophage and
+
polarization to M2 protumor subtype, which impairs responses of CD8 T cell to HBV and lead to virus
[79]
persistence . Moreover, macrophages produce matrix metalloproteinase 9 (MMP9) and IL-23 under
the stimulation of HBV, which blocks binding of IFN-α to IFNAR1 and facilitate tumor angiogenesis and
progression [80,81] .

Contrarily, pro-inflammatory macrophages are essential for progression of NASH-associated HCC. In a
high-fat diet (HFD) zebrafish model, hepatic macrophage morphology is changed and number of TNF-α
positive positive macrophages is increased, and liver size is subsequently reduced in macrophage-ablation
[82]
NAFLD/NASH associated HCC larvae but not in HCC or NAFLD alone . The process from NAFLD to
HCC is proximately accompanied by inflammation and fibrosis, in which, innate and adaptive immune cells
are enriched and trafficking in liver. A recent study demonstrates that KCs induce recruitment of platelet in
early stage of NAFLD, which is associated with hepatic injury. Furthermore, antiplatelet treatment abrogates
+
+
+
infiltration of CD8 T cells, Ly6G granulocytes, especially CD11b F4/80 monocyte-derived macrophages
+
[83]
and KCs, which alleviates the progression of carcinogenesis .Mechanistically, excessive toxic lipids and
cholesterol crystals accumulate in macrophages, forcing cells polarization to pro-inflammatory phenotype,
and depletion of KCs dampens release of pro-inflammatory cytokines and liver damage [84-87] . Meanwhile,
[88]
lipotoxic hepatocytes activate macrophages polarization via releasing exosomes containing miR-192-5p .
Generally, NF-κB and JNK signaling pathways mainly mediate the activation of macrophages towards
the pro-inflammatory phenotype. Stimulator of interferon genes (STING) invokes the polarization of
macrophage to produce TNF-α and IL-1β via JNK/NF-κB pathways, which further modulate increase lipid
[89]
deposition in hepatocytes and exacerbate progression of NAFLD .
MDSCs
MDSCs, generated as immature myeloid cells from bone marrow, are the major immunosuppressive cells
which inhibit T cells proliferation and function and enhance induction of Treg cells and tumor-associated
macrophages in chronic inflammation and cancers. Multiple studies have reported that MDSCs are closely
related with HBV persistence and HCC. In patients with chronic HBV infection (CHB), HBeAg induces
expansion of monocytic MDSCs (mMDSCs) via indoleamine-2,3-dioxygenase (IDO), to suppress autologous
[90]
T cell proliferation and IFN-γ production, favoring the establishment of tolerant immune environment .
Similarly, HBsAg promotes differentiation of mMDSCs through activation of ERK/IL-6/STAT3 signaling
[91]
feedback . Mechanistically, cell cycle-related kinase (CCRK), as a direct AR-regulated oncogene,
[92]
mediates virus-host signaling to promote progression of HBV-associated HCC , and further induces
[93]
polymorphonuclear (PMN) MDSCs in HCC . Moreover, AR-CCRK pathway is consistently shared by
tumorigenesis in NASH-related HCC. Induction of CCRK activates mTORC1/4E-BP1/S6K/SREBP1 cascades
and recruits PMN MDSCs to initiate metabolic reprogramming and immunosuppressive microenvironment
[94]
to facilitate the progression of HCC . Concordantly, hepatic lipid deposit promotes accumulation of
MDSCs and further enhances the cellular production of ROS in NASH-model mice [95,96] .

NK cells
Lymphocytes represent another crucial population in intrahepatic innate immune cells, including NKT cells,
ILCs (NK cells and other ILC subpopulations) and γδT cells. NKT and NK cells, which mainly contain
conventional circulating NK and liver-resident NK cells, comprise about 50% of lymphocytes in liver.
Generally, hepatic NK cells recognize and restrain virus-infected cells via direct cytotoxicity or secreting