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Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH − / − MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH +/+ littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration. Factor H (FH), one of the most abundant plasma proteins, is the major soluble inhibitor of the alternative complement pathway. Apoptotic cells bind FH while triggering complement activation by binding of C1 complex, which ensures efficient opsonization and removal of apoptotic debris but prevents excessive complement activation and inflammation. 1,2 Dysregulation of complement contributes significantly to the pathology of many diseases. 3 Recently, novel roles and intracellular location for complement have been identified suggesting that its functions exceed our current understanding. 4 After previously identifying the ligands for FH on the apoptotic cell surface as dsDNA, histones and annexin A2, 5 we sought to explore the functional consequences of the FH-apoptotic cell interaction in the context of the chronic autoimmune disorder systemic lupus erythematosus (SLE) and age-related macular degeneration (AMD). Aberrant apoptosis and impaired clearance of apoptotic cells are of central importance in the pathogenesis of SLE and lead to formation of autoantibodies. 6-8 Anti-chromatin autoantibodies are a hallmark of SLE and anti-annexin A2 autoantibodies are also frequently observed in SLE patients. 9 Interestingly, the corresponding autoantigens are exactly those that we identified as ligands for FH on the apoptotic cell surface, suggesting a possibility of disturbance of FH function in SLE. Glomerulonephritis is one typical manifestation of human SLE 10 and mutations in FH and another complement inhibitor CD46 are associated with earlier onset of nephritis in SLE patients. 11 FH-deficient (CFH − / − ) mice spontaneously develop membranoproliferative glomerulonephritis, which is dependent on C3 activation. 12 When crossed with the MRL-lpr mouse strain, a model of lupus, the originated CFH − / − MRLlpr mice exhibit accelerated lupus nephritis and die at younger age than their CFH +/+ MRL-lpr littermates. 13,14 AMD is the leading cause of visual impairm...

It is widely accepted that silver nanoparticles (AgNPs) are toxic to biological systems. However, little is known about their actions at molecular level and the cytophysiological effects after AgNP removal. As nanoparticles are suggested a promising tool to transport drugs to the brain for use in neurological conditions, we used HT22 mouse hippocampal neuronal cells as a model to study AgNP-mediated effects after their removal from the cell culture medium. We selected a relatively low concentration of AgNPs, 5 μg/ml, treated the cells for 48 h, and evaluated AgNP-induced cytophysiological effects after 96 h of AgNP removal. AgNP removal did not result in cytotoxicity. In contrast, AgNPs modulated HT22 cell cycle and proliferation and induced oxidative stress and 53BP1 recruitment, which were accompanied by elevated levels of p53 and p21. AgNP-associated diminution in lamin B1 pools did not significantly affect the structure of the nucleus. No disruption in F-actin dynamics was observed upon AgNP treatment. Moreover, we showed for the first time that AgNPs stimulated changes in DNA methylation: the augmentation in 5-methylcytosine (5-mC) and DNMT1, DNMT2, DNMT3a, and DNMT3b levels were observed. The upregulation of DNMT2 may be a part of cellular stress response to AgNP treatment. Taken together, AgNP removal resulted in p53/p21-mediated inhibition of cell proliferation, oxidant-based DNA damage response, and changes in DNA methylation patterns, which suggests that more attention should be paid to the possible outcomes in individuals exposed to nano-sized biomaterials.

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Main conclusion The changes in the expression of key sugar metabolism enzymes (SPS and SUS), sucrose content and arrangement of chloroplast starch may play a significant role in the cold response in M. giganteus and maize plants.