HCV inhibits M2a, M2b and M2c macrophage polarization via HCV core protein engagement with Toll‑like receptor 2

Abstract

Hepatitis C virus (HCV) establishes a persistent infection in most patients, eventually leading to chronic hepatitis C (CHC), cirrhosis and hepatocellular carcinoma. Our previous study revealed that HCV core protein (HCVc) inhibited the differentiation of monocytes into M1 and M2 macrophages. However, it remains unclear as to whether HCVc affects the polarization of M2 macrophages, and if this effect promotes the progression of chronic disease. In the present study, peripheral blood mononuclear cells (PBMCs) from patients with CHC and healthy controls (HCs) were isolated, purified and polarized to M2a, M2b and M2c macrophages. Phenotypic expression, cytokine secretion and gene expression were analyzed using flow cytometry, ELISA and reverse transcription-quantitative polymerase chain reaction, respectively. Monocytes from HCs were cultured with HCVc to study the effect of HCVc on macrophage polarization. Plasma alanine transaminase and HCV-RNA levels were significantly higher, and albumin levels were significantly lower in the CHC group than those in the control group (P<0.05). M2a macrophages polarized from monocytes of patients with CHC expressed lower levels of CD209, IL-1 receptor antagonist (IL-1RA) and Fizz1 compared with those from HCs. M2b macrophages expressed lower levels of CD86 and TNF-α, and M2c macrophages expressed lower levels of CD163, TGF-β and sphingosine kinase 1 (SPHK1) in the CHC group compared with HCs (P<0.05). HCVc inhibited the expression levels of CD209, IL-1RA and Fizz1 in M2a macrophages; CD86 and TNF-α in M2b macrophages; and CD163, TGF-β and SPHK1 in M2c macrophages (P<0.05). HCVc significantly suppressed phagocytosis of all subtypes (P<0.05); however, this inhibition was restored by an anti-Toll-like receptor (TLR)2 antibody (P<0.05). In conclusion, HCVc inhibited monocyte-derived M2a, M2b and M2c subtype differentiation via the TLR2 signaling pathway, resulting in macrophages exhibiting reduced phagocytosis in patients with CHC. This may contribute to persistent HCV infection, thus suggesting that the blockade of HCVc may be a new therapeutic approach for the treatment of HCV infection.

Hepatitis C Virus Infection Upregulates Plasma Phosphosphingolipids and Endocannabinoids and Downregulates Lysophosphoinositols

“…Finally, the polarization of M2 macrophages into M2a, M2b, and M2c subtypes has been investigated with respect to HCV. M2c macrophages polarized from patients with chronic hepatitis C, expressed lower levels of SPHK1 than those from healthy controls [ 57 ]. Our plasma lipidomic findings of elevated d16:1, d18:1, and d19:1 S1P concentrations in HCV patients reflect holistic SPHK1 and SPKH2 activities, not simply that which is in M2c macrophages.…”

Tumor-derived extracellular vesicles regulate macrophage polarization: role and therapeutic perspectives

“…M2 macrophages have a low antigen-presenting ability and mostly release anti-inflammatory factors ( 39 ). IL-4 or IL-13 can effectively counteract inflammatory damage and promote tissue healing by stimulating macrophages to differentiate into M2a cells and release anti-inflammatory cytokines such as IL-1RA, IL-10, and transforming growth factor-beta (TGF-β) ( 40 , 41 ) via the co-receptor IL-4Rα. Arg1, Mrc1, Chil3, and Retnla are their primary markers of detection ( 42 ).…”

“…When TLR or IL-1R agonists are exposed to the body, they produce M2b macrophages that release cytokines, IL-10, IL-1, etc., to exert immunomodulatory effects. Major histocompatibility complex II (MHC II), CD86, etc., are their primary monitoring markers ( 41 , 43 ). IL-10 helps macrophages become M2c.…”

Monocytes and Macrophages in Kidney Disease and Homeostasis

“…Macrophages are also observed in several renal diseases in animal models used for pathogenetic investigation [3][4][5][6][7][8][9]. Table 3 [10][11][12], provides the immuno-phenotypic markers used to identify major macrophage morphologic subtypes. These markers, however, are not subtype-specific, with a complex overlap between markers and cell types, highlighting the challenges in the interpretation of functional significance [2,10].…”