Abstract
The calcium-binding protein S100A4 has been described to promote pathological inflammation in experimental autoimmune and inflammatory disorders and in allergy and to contribute to antigen presentation and antibody response after parenteral immunization with an alum-adjuvanted antigen. In this study, we extend these findings by demonstrating that mice lacking S100A4 have a defective humoral and cellular immune response to mucosal (sublingual) immunization with a model protein antigen [ovalbumin (OVA)] given together with the strong mucosal adjuvant cholera toxin (CT), and that this impairment is due to defective adjuvant-stimulated antigen presentation by antigen-presenting cells. In comparison to wild-type (WT) mice, mice genetically lacking S100A4 had reduced humoral and cellular immune responses after immunization with OVA plus CT, including a complete lack of detectable germinal center reaction. Further, when stimulated in vitro with OVA plus CT, S100A4−/− dendritic cells (DCs) showed impaired responses in several CT-stimulated immune regulatory molecules including the co-stimulatory molecule CD86, inflammasome-associated caspase-1 and IL-1β. Coculture of OVA-specific OT-II T cells with S100A4−/− DCs that had been pulse incubated with OVA plus CT resulted in impaired OT-II T cell proliferation and reduced production of Th1, Th2, and Th17 cytokines compared to similar cocultures with WT DCs. In accordance with these findings, transfection of WT DCs with S100A4-targeting small interfering RNA (siRNA) but not mock-siRNA resulted in significant reductions in the expression of caspase-1 and IL-1β as well as CD86 in response to CT. Importantly, also engraftment of WT DCs into S100A4−/− mice effectively restored the immune response to immunization in the recipients. In conclusion, our results demonstrate that deficiency in S100A4 has a strong impact on the development of both humoral and cellular immunity after mucosal immunization using CT as adjuvant.
Highlights
S100A4 is one of more than 20 structurally related calciumbinding proteins of the S100 protein family, which have intracellular as well as extracellular functions [1, 2]
In the OVA plus cholera toxin (CT)-immunized WT mice, there was a marked increase in the number of T effector cells (Foxp3−CD25+CD4+) in response to immunization, which was absent in immunized S100A4−/− mice (Figure 1C)
We demonstrate that S100A4 is important for efficient induction of adaptive immune responses after s.l. immu nization with the model protein antigen OVA given together with the strong mucosal adjuvant CT
Summary
S100A4 is one of more than 20 structurally related calciumbinding proteins of the S100 protein family, which have intracellular as well as extracellular functions [1, 2]. S100A4 is expressed in many normal cells, including fibroblasts, endothelial cells, smooth muscle cells, lymphocytes, neutrophils, and macrophages [3,4,5]. S100A4 has been found to regulate a diverse range of cellular processes such as cell growth and survival, differentiation, and motility [6]. Oriented research on S100A4 has been largely focused on its cancer metastasis-promoting properties [3, 7, 8], and its role in promoting pathological inflammation in rheumatoid arthritis [9, 10], cardiovascular disease [11], fibrotic diseases [12, 13], and experimental autoimmune encephalomyelitis [14]. Loss of S100A4 has been shown to impair macrophage recruitment and chemotactic motility to sites of inflammation in vivo [4]. We identified a central role for S100A4 in allergy [15]
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