Chronic liver inflammation and hepatocellular carcinogenesis are independent of S100A9

Abstract

The S100A8/A9 heterodimer (calprotectin) acts as a danger signal when secreted into the extracellular space during inflammation and tissue damage. It promotes proinflammatory responses and drives tumor development in different models of inflammationdriven carcinogenesis. S100A8/A9 is strongly expressed in several human tumors, including hepatocellular carcinoma (HCC). Apart from this evidence, the role of calprotectin in hepatocyte transformation and tumor microenvironment is still unknown. The aim of this study was to define the function of S100A8/A9 in inflammation-driven HCC. Mice lacking S100a9 were crossed with the Mdr2 2/2 model, a prototype of inflammation-induced HCC formation. S100a9 2/2 Mdr2 2/2 (dKO) mice displayed no significant differences in tumor incidence or multiplicity compared to Mdr2 2/2 animals. Chronic liver inflammation, fibrosis and oval cell activation were not affected upon S100a9 deletion. Our data demonstrate that, although highly upregulated, calprotectin is dispensable in the onset and development of HCC, and in the maintenance of liver inflammation.S100A8 and S100A9 are members of the S100 family, consisting of low molecular weight EF-hand motif calcium binding proteins. 1 They act predominantly as heterodimer, termed calprotectin. Intracellular S100A8/A9 controls different homeostatic processes and cytoskeletal rearrangements. In response to cell activation or damage, both proteins are released into the extracellular space and function as danger signal by binding to different receptors, including toll-like receptor 2 and 4 (TLR2 and TLR4), and the receptor for advanced glycation end products (RAGE). 2,3Under physiological conditions, constitutive expression of S100A8/A9 is mainly restricted to myeloid cells, including neutrophils and monocytes. 4 However, during inflammatory processes and cell damage, prominent expression is also observed in epithelial and endothelial cells. Increased levels of S100A8 and S100A9 are documented in several chronic inflammatory disorders, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, cystic fibrosis and psoriasis. In these settings, both proteins amplify proinflammatory responses by promoting leukocyte migration and inducing the release of cytokines and chemokines.

Calprotectin may be positively associated with the severity of acne vulgaris

“…26 Calprotectin released by keratinocytes, phagocytes, monocytes, granulocytes and vascular cells is recognized by toll-like receptors (TLRs) to induce inflammatory response. 27,28 Our results indicated a high calprotectin concentration might be associated with the inflammatory responses of acne, which is in line with the data from previous studies. 29,30 Higher calprotectin was also evidenced in many other inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, neonatal sepsis, and multiple sclerosis.…”

Calprotectin can play an inflammatory role in acne vulgaris

“…Calprotectin is released from keratinocytes along with activated monocytes, phagocytes, granulocytes and vascular cells. Calprotectin is recognized by TLRs and induces inflammation [ 11 , 12 ], but calprotectin has not been evaluated in AV patients before. In this study, the serum calprotectin level of patients with AV was statistically significantly higher than that of the healthy controls.…”

S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma

“…In vivo, the impact of S100A9 on intrinsic liver tumor development appears however more complex. Indeed, tumor cell proliferation in S100A9 genetically deficient mice was unaffected in an Mdr2 −/− inflammation-driven HCC mouse model [ 159 ], whereas tumor cell proliferation was decreased in a DEN-induced HCC model developing in the absence of chronic inflammation [ 44 ]. Thus, here again, the roles and functions of S100A8/A9 dimers in hepatic carcinogenesis appear complex and multiple.…”