An LGG-derived protein promotes IgA production through upregulation of APRIL expression in intestinal epithelial cells

Abstract

p40, a Lactobacillus rhamnosus GG (LGG)-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells, leading to amelioration of intestinal injury and inflammation. To elucidate mechanisms by which p40 regulates mucosal immunity to prevent inflammation, this study aimed to determine the effects and mechanisms of p40 on regulation of a proliferation-inducing ligand (APRIL) expression in intestinal epithelial cells for promoting IgA production. p40 up-regulated April gene expression and protein production in mouse small intestine epithelial (MSIE) cells, which were inhibited by blocking EGFR expression and kinase activity. Enteroids from Egfrfl/fl , but not Egfrfl/fl-Vil-Cre mice with EGFR specifically deleted in intestinal epithelial cells, exhibited increased April gene expression by p40 treatment. p40-conditioned media from MSIE cells increased B cell class switching to IgA+ cells and IgA production, which was suppressed by APRIL receptor neutralizing antibodies. Treatment of B cells with p40 did not show any effects on IgA production. p40 treatment increased April gene expression and protein production in small intestinal epithelial cells, fecal IgA levels, IgA+B220+, IgA+CD19+, and IgA+ plasma cells in lamina propria of Egfrfl/fl, but not Egfrfl/fl-Vil-Cre mice. Thus, p40 up-regulates EGFR-dependent APRIL production in intestinal epithelial cells, which may contribute to promoting IgA production.

Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems

“…Host and microbial factors, which stimulate production of IgA-promoting cytokines (i.e., BAFF and TGF-β) by epithelial cells enhance production of SIgA (34). The pIgR which mediate the transepithelial transport of polymeric IgA and secretion of SIgA is expressed by different type of epithelial cells and the resolution of its crystal structure provides new information about multiple conformations used by the secretory component to protect mammals from pathogens (35).…”

Epithelial-microbial diplomacy: escalating border tensions drive inflammation in inflammatory bowel disease

“…Commensal bacteria can promote IgA production directly through bacterial proteins binding host receptors on IECs, and indirectly through microbial metabolites such as short-chain fatty acids (SCFAs) binding the GPR43 receptor. 40,41 In turn, IgA binding to commensals can promote their colonization and stability within their colonization niche. [42][43][44] A continuing question in the field is how host responses differentiate between commensal and pathogenic microorganisms.…”

“…99 In addition, p40 can also modulate IgA production by increased expression of a proliferation-inducing ligand in IECs. 41 More recently, p40 was found to exert its responses through the epidermal growth factor receptor in neonatal mice, ultimately promoting IgA production and T regulatory cell (Treg) differentiation in adult mice. 100…”

<i>Lactobacillus rhamnosus GG:</i> experience in pediatric gastroenterology

“…Многочисленные исследования in vitro и in vivo показывают влияние LGG на неспецифическое повышение иммунитета [12], усиление противовоспалительного типа ответа, снижение секреции провоспалительных цитокинов [13]. Это вызывает интерес исследователей к проведению рандомизированных контролируемых исследований (РКИ) для оценки эффективности применения LGG у детей с различными проявлениями аллергии, атопическим дерматитом, в период повышения сезонных респираторных заболеваний, в отношении формирования поствакцинального иммунитета и т.д.…”