Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2020-08-12 , DOI: 10.1016/j.bbadis.2020.165922 Alessandra Fraternale 1 , Carolina Zara 1 , Tomas Di Mambro 1 , Elisabetta Manuali 2 , Domenica Anna Genovese 2 , Luca Galluzzi 1 , Aurora Diotallevi 1 , Andrea Pompa 1 , Francesca De Marchis 3 , Patrizia Ambrogini 1 , Erica Cesarini 1 , Francesca Luchetti 1 , Michaël Smietana 4 , Kathy Green 5 , Francesca Bartoccini 1 , Mauro Magnani 1 , Rita Crinelli 1
Excessive production of immunoglobulins (Ig) causes endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR). Hypergammaglobulinemia and lymphadenopathy are hallmarks of murine AIDS that develops in mice infected with the LP-BM5 murine leukemia retrovirus complex. In these mice, Th2 polarization and aberrant humoral response have been previously correlated to altered intracellular redox homeostasis. Our goal was to understand the role of the cell's redox state in Ig secretion and plasma cell (PC) maturation. To this aim, LP-BM5-infected mice were treated with I-152, an N-acetyl-cysteine and cysteamine supplier. Intraperitoneal I-152 administration (30 μmol/mouse three times a week for 9 weeks) decreased plasma IgG and increased IgG/Syndecan 1 ratio in the lymph nodes where IgG were in part accumulated within the ER. PC containing cytoplasmic inclusions filled with IgG were present in all animals, with fewer mature PC in those treated with I-152. Infection induced up-regulation of signaling molecules involved in the UPR, i.e. CHAC1, BiP, sXBP-1 and PDI, that were generally unaffected by I-152 treatment except for PDI and sXBP-1, which have a key role in protein folding and PC maturation, respectively. Our data suggest that one of the mechanisms through which I-152 can limit hypergammaglobulinemia in LP-BM5-infected mice is by influencing IgG folding/assembly as well as secretion and affecting PC maturation.
中文翻译:
I-152是N-乙酰半胱氨酸和半胱胺的供应商,通过影响未折叠的蛋白应答,可抑制LP-BM5鼠白血病逆转录病毒感染小鼠的免疫球蛋白分泌和浆细胞成熟。
免疫球蛋白(Ig)的过量产生会引起内质网(ER)应激,并触发未折叠的蛋白质反应(UPR)。高丙种球蛋白血症和淋巴结病是鼠AIDS的标志,它在被LP-BM5鼠白血病逆转录病毒复合体感染的小鼠中发展。在这些小鼠中,Th2极化和异常的体液反应先前已与改变的细胞内氧化还原稳态相关。我们的目标是了解细胞氧化还原状态在Ig分泌和浆细胞(PC)成熟中的作用。为此,用I-152(一种N-乙酰半胱氨酸和半胱胺供应商。腹膜内I-152给药(每周30次,每次3μmol,共9周)降低了IgG,并增加了ER内部分积累IgG的淋巴结中IgG / Syndecan 1的比例。在所有动物中均存在含有充满IgG的PC内含物的PC,而用I-152治疗的PC中成熟PC较少。感染导致UPR中涉及的信号分子(即CHAC1,BiP,sXBP-1和PDI)上调,这些分子通常不受I-152处理的影响,但PDI和sXBP-1在蛋白质折叠和降解中起关键作用PC分别成熟。我们的数据表明,I-152可以通过限制IgG折叠/组装以及分泌和影响PC成熟来限制LP-BM5感染小鼠中的高球蛋白血症的机制之一。