Keratitis induced by Pseudomonas aeruginosa (P. aeruginosa) is an acute and serious corneal inflammation. As a family of gene regulators, miRNAs play a crucial role in modulating host response after microbial invasion. However, their functions in P. aeruginosa keratitis remain largely unclear. In the present study, we demonstrated that miR-155 expression was significantly increased in macrophages and corneal tissue after P. aeruginosa infection. In vivo studies demonstrated that mice with miR-155 knockdown displayed more resistance to P. aeruginosa keratitis, with a lower bacterial burden. In addition, in vitro and in vivo studies indicated that miR-155 enhanced apoptosis of macrophages after P. aeruginosa infection, and resulted in a susceptible phenotype of P. aeruginosa keratitis. Moreover, miR-155 induced apoptosis through reducing activation of PI3K-Akt signaling pathway. Our data provided evidence of miR-155 mediated apoptosis of macrophage in P. aeruginosa keratitis, which may be an underlying target for the therapy of P. aeruginosa keratitis and other infectious diseases.
© 2024 The Authors.

The proliferation and differentiation of antigen-specific B cells, including the generation of germinal centers (GC), are prerequisites for long-lasting, antibody-mediated immune protection. Affinity for antigen determines B cell recruitment, proliferation, differentiation, and competitiveness in the response, largely through determining access to T cell help. However, how T cell-derived signals contribute to these outcomes is incompletely understood. Here, we report how the signature cytokine of follicular helper T cells, IL-21, acts as a key regulator of the initial B cell response by accelerating cell cycle progression and the rate of cycle entry, increasing their contribution to the ensuing GC. This effect occurs over a wide range of initial B cell receptor affinities and correlates with elevated AKT and S6 phosphorylation. Moreover, the resultant increased proliferation can explain the IL-21-mediated promotion of plasma cell differentiation. Collectively, our data establish that IL-21 acts from the outset of a T cell-dependent immune response to increase cell cycle progression and fuel cyclic re-entry of B cells, thereby regulating the initial GC size and early plasma cell output.
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.

Humoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL-21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in the G1 cell cycle stage in the GC LZ. Cell cycle progression of DZ B cells is unaffected by IL-21 availability, as is the zone phenotype of the most highly proliferative GC B cells. Collectively, this study characterises the development of GC zones as a function of time and B cell proliferation and identifies IL-21 as an important regulator of these processes. These data help explain the requirement for IL-21 in normal antibody affinity maturation.
© 2021. The Author(s).

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the development of autoantibodies that drive disease pathogenesis. Genetic studies have associated nonsynonymous variants in the BANK1 B cell scaffolding gene with susceptibility to SLE and autoantibodies in lupus. To determine how the BANK1 SLE-risk variants contribute to the dysregulated B cell program in lupus, we performed genotype/phenotype studies in human B cells. Targeted phospho-proteomics were used to evaluate BCR/CD40 signaling in human B cell lines engineered to express the BANK1 risk or non-risk variant proteins. We found that phosphorylation of proximal BCR signaling molecules was reduced in B cells expressing the BANK1 risk protein compared to the non-risk protein. Similar to these findings, we observed decreased B cell signaling in primary B cells from genotyped healthy control subjects carrying the BANK1 risk haplotype, including blunted BCR- and CD40-dependent AKT activation. Consistent with decreased AKT activation, we found that BANK1 risk B cells expressed increased basal levels of FOXO1 protein and increased expression of FOXO1 target genes upon stimulation compared to non-risk B cells. Healthy subjects carrying the BANK1 risk haplotype were also characterized by an expansion of memory B cells. Taken together, our results suggest that the SLE susceptibility variants in the BANK1 gene may contribute to lupus by altering B cell signaling, increasing FOXO1 levels, and enhancing memory B cell development.
Copyright © 2016 Elsevier Inc. All rights reserved.