Liver myofibroblasts regulate the phenotype and function of monocytes through soluble factors in cirrhosis

Zhang,Min; Wang,Feng‑Lan; Zhu,Jian‑Yun; Zheng,Yu‑Bao; Zhao,Qi‑Yi; Gu,Yu‑Rong; Zhang,Qi; Chong,Yu‑Tian; Gao,Zhi‑Liang

doi:10.3892/etm.2012.767

Liver myofibroblasts regulate the phenotype and function of monocytes through soluble factors in cirrhosis

Authors:
- Min Zhang
- Feng‑Lan Wang
- Jian‑Yun Zhu
- Yu‑Bao Zheng
- Qi‑Yi Zhao
- Yu‑Rong Gu
- Qi Zhang
- Yu‑Tian Chong
- Zhi‑Liang Gao
View Affiliations

Affiliations: Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, P.R. China, Department of Infectious Diseases, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, P.R. China, Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat‑sen University, Guangzhou, P.R. China
Published online on: October 25, 2012 https://doi.org/10.3892/etm.2012.767
Pages: 143-149

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The ability of lymphocytes and macrophage‑derived cytokines and chemokines to modulate the activation of stromal cells during immune responses is well‑documented, but few studies have investigated whether liver myofibroblasts shape the phenotype and function of monocytes in liver disease. In the present study, Kupffer cells were demonstrated to be activated in the inflamed livers of patients with cirrhosis and be in close contact with liver myofibroblasts. The Kupffer cells from cirrhotic livers expressed significantly elevated levels of PD‑L1 (also termed B7‑H1), TLR4, CD80, CD32 and CD64 relative to those from normal livers. Consistent with this finding, the expression of these surface molecules was significantly upregulated in monocytes following exposure to liver myofibroblasts originating from inflamed livers. Accordingly, the liver myofibroblast‑exposed monocytes exhibited a significant increase in dextran endocytosis. These data reveal that bidirectional interactions between liver myofibroblasts and Kupffer cells may function as an ‘amplification loop’ to enhance inflammation further in the liver. Liver myofibroblasts are central in the pathogenesis of liver diseases and should be considered as targets for the rational design of effective immune‑based anti‑inflammation therapies. Furthermore, it was also demonstrated that skin fibroblasts were as effective as liver myofibroblasts at inducing monocyte activation, suggesting that fibroblasts, which are numerous in the body, may represent an underrated cell population that is actively involved in immunomodulatory functions.

View Figures

View References

1	Naito M, Hasegawa G, Ebe Y and Yamamoto T: Differentiation and function of Kupffer cells. Med Electron Microsc. 37:16–28. 2004. View Article : Google Scholar
2	Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA and Schwabe RF: TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 13:1324–1332. 2007. View Article : Google Scholar : PubMed/NCBI
3	Heymann F, Hammerich L, Storch D, et al: Hepatic macrophage migration and differentiation critical for liver fibrosis is mediated by the chemokine receptor C-C motif chemokine receptor 8 in mice. Hepatology. 55:898–909. 2012. View Article : Google Scholar : PubMed/NCBI
4	Kolios G, Valatas V and Kouroumalis E: Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol. 12:7413–7420. 2006.PubMed/NCBI
5	Mosser DM and Edwards JP: Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 8:958–969. 2008. View Article : Google Scholar : PubMed/NCBI
6	Bilzer M, Roggel F and Gerbes AL: Role of Kupffer cells in host defense and liver disease. Liver Int. 26:1175–1186. 2006. View Article : Google Scholar : PubMed/NCBI
7	Heymann F, Trautwein C and Tacke F: Monocytes and macrophages as cellular targets in liver fibrosis. Inflamm Allergy Drug Targets. 8:307–318. 2009. View Article : Google Scholar : PubMed/NCBI
8	Henderson NC and Iredale JP: Liver fibrosis: cellular mechanisms of progression and resolution. Clin Sci (Lond). 112:265–280. 2007. View Article : Google Scholar : PubMed/NCBI
9	Reeves HL and Friedman SL: Activation of hepatic stellate cells - a key issue in liver fibrosis. Front Biosci. 7:d808–d826. 2002. View Article : Google Scholar : PubMed/NCBI
10	Bataller R and Brenner DA: Liver fibrosis. J Clin Invest. 115:209–218. 2005. View Article : Google Scholar
11	Holt AP, Haughton EL, Lalor PF, Filer A, Buckley CD and Adams DH: Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology. 136:705–714. 2009. View Article : Google Scholar : PubMed/NCBI
12	Chinnadurai R and Grakoui A: B7-H4 mediates inhibition of T cell responses by activated murine hepatic stellate cells. Hepatology. 52:2177–2185. 2010. View Article : Google Scholar : PubMed/NCBI
13	Schildberg FA, Wojtalla A, Siegmund SV, et al: Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism. Hepatology. 54:262–272. 2011. View Article : Google Scholar : PubMed/NCBI
14	Muhanna N, Horani A, Doron S and Safadi R: Lymphocyte-hepatic stellate cell proximity suggests a direct interaction. Clin Exp Immunol. 148:338–347. 2007. View Article : Google Scholar : PubMed/NCBI
15	Braet F and Wisse E: Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol. 1:12002. View Article : Google Scholar : PubMed/NCBI
16	Thomson AW and Knolle PA: Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 10:753–766. 2010. View Article : Google Scholar : PubMed/NCBI
17	Zimmermann HW, Seidler S, Nattermann J, et al: Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One. 5:e110492010. View Article : Google Scholar : PubMed/NCBI
18	Orimo A, Gupta PB, Sgroi DC, et al: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121:335–348. 2005. View Article : Google Scholar
19	Zheng L, He M, Long M, Blomgran R and Stendahl O: Pathogen-induced apoptotic neutrophils express heat shock proteins and elicit activation of human macrophages. J Immunol. 173:6319–6326. 2004. View Article : Google Scholar : PubMed/NCBI
20	Unitt E, Rushbrook SM, Marshall A, et al: Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology. 41:722–730. 2005. View Article : Google Scholar : PubMed/NCBI
21	Kalluri R and Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 6:392–401. 2006. View Article : Google Scholar
22	Schwabe RF, Seki E and Brenner DA: Toll-like receptor signaling in the liver. Gastroenterology. 130:1886–1900. 2006. View Article : Google Scholar : PubMed/NCBI
23	Seki E, Tsutsui H, Nakano H, et al: Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta. J Immunol. 166:2651–2657. 2001. View Article : Google Scholar
24	Duffield JS, Forbes SJ, Constandinou CM, et al: Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 115:56–65. 2005. View Article : Google Scholar : PubMed/NCBI
25	Rivera CA, Bradford BU, Hunt KJ, et al: Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol. 281:G200–G207. 2001.PubMed/NCBI
26	Roberts RA, Ganey PE, Ju C, Kamendulis LM, Rusyn I and Klaunig JE: Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci. 96:2–15. 2007. View Article : Google Scholar : PubMed/NCBI
27	Cassiman D, Libbrecht L, Desmet V, Denef C and Roskams T: Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol. 36:200–209. 2002. View Article : Google Scholar : PubMed/NCBI
28	Magness ST, Bataller R, Yang L and Brenner DA: A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology. 40:1151–1159. 2004. View Article : Google Scholar : PubMed/NCBI
29	Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA and Alison MR: A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology. 126:955–963. 2004. View Article : Google Scholar : PubMed/NCBI
30	Buckley CD, Pilling D, Lord JM, Akbar AN, Scheel-Toellner D and Salmon M: Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol. 22:199–204. 2001. View Article : Google Scholar : PubMed/NCBI
31	De Minicis S, Seki E, Uchinami H, Kluwe J, Zhang Y, Brenner DA and Schwabe RF: Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology. 132:1937–1946. 2007.PubMed/NCBI
32	Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M and Ley K: Development of monocytes, macrophages, and dendritic cells. Science. 327:656–661. 2010. View Article : Google Scholar : PubMed/NCBI
33	Kuang DM, Zhao Q, Peng C, et al: Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 206:1327–1337. 2009. View Article : Google Scholar : PubMed/NCBI
34	Viñas O, Bataller R, Sancho-Bru P, et al: Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology. 38:919–929. 2003.PubMed/NCBI