In a manner dependent on CD4 T cell help and Toll-like receptor signals, B cells lacking WASp induce autoantibody production and autoimmune disease in mice.

The activation of the B-cell receptor (BCR), which initiates B-cell activation, is triggered by antigen-induced self-aggregation and clustering of receptors at the cell surface. While antigen-induced actin reorganization is known to be involved in BCR clustering in response to membrane-associated antigen, the underlying mechanism that links actin reorganization to BCR activation remains unknown. Here we show that both the stimulatory Bruton’s tyrosine kinase (Btk) and the inhibitory SH2-containing inositol-5 phosphatase-1 (SHIP-1) are required for efficient BCR self-aggregation. In Btk-deficient B cells, the magnitude of BCR aggregation into clusters and B-cell spreading in response to antigen-tethered lipid bilayer is drastically reduced, compared to that observed in wild type B-cells. In SHIP-1−/− B-cells, while surface BCRs aggregate into microclusters, the centripetal movement and growth of BCR clusters are inhibited and B-cell spreading is increased. The persistent BCR microclusters in SHIP−/− B-cells exhibit higher levels of signaling than merged BCR clusters. Contrast to the inhibition of actin remodeling in Btk-deficient B-cells, actin polymerization, F-actin accumulation, and WASP phosphorylation are enhanced in SHIP-1−/− B-cells in a Btk-dependent manner. Thus, a balance between positive and negative signaling regulates the spatiotemporal organization of the BCR at the cell surface by controlling actin remodeling, which potentially regulates the signal transduction of the BCR. This study suggests a novel feedback loop between BCR signaling and the actin cytoskeleton.

A cell biology study using conditional gene knockout mouse models reveals a novel mechanism by which the actin cytoskeleton negatively regulates the signal transduction of the B cell antigen receptor.

B-cells encounter both soluble (sAg) and membrane-associated antigens (mAg) in the secondary lymphoid tissue, yet how the physical form of Ag modulates B-cell activation remains unclear. This study compares actin reorganization and its role in BCR signalosome formation in mAg- and sAg-stimulated B-cells. Both mAg and sAg induce F-actin accumulation and actin polymerization at BCR microclusters and at the outer rim of BCR central clusters, but the kinetics and magnitude of F-actin accumulation in mAg-stimulated B-cells are greater than those in sAg-stimulated B-cells. Accordingly, the actin regulatory factors, cofilin and gelsolin, are recruited to BCR clusters in both mAg- and sAg-stimulated B-cells but with different kinetics and patterns of cellular redistribution. Inhibition of actin reorganization by stabilizing F-actin inhibits BCR clustering and tyrosine phosphorylation induced by both forms of Ag. Depolymerization of F-actin leads to unpolarized microclustering of BCRs and tyrosine phosphorylation in BCR microclusters without mAg and sAg, but in much slower kinetics than those induced by Ag. Therefore, actin reorganization, mediated via both polymerization and depolymerization, is required for the formation of BCR signalosomes in response to both mAg and sAg.

SUMMARY Overnutrition activates proinflammatory program in macrophages to induce insulin resistance (IR), but its molecular mechanisms remain incompletely understood. Here we show that saturated fatty acid and lipopolysaccharide, two factors implicated in high-fat diet (HFD)-induced IR, suppress macrophage CGI-58 expression. Macrophage-specific CGI-58 knockout (MaKO) in mice aggravates HFD-induced glucose intolerance and IR, which is associated with augmented systemic/tissue inflammation and proinflammatory activation of adipose tissue macrophages. CGI-58-deficient macrophages exhibit mitochondrial dysfunction due to defective peroxisome proliferator-activated receptor (PPAR)-γ signaling. Consequently they overproduce reactive oxygen species (ROS) to potentiate secretion of proinflammatory cytokines by activating NLRP3 inflammasome. Anti-ROS treatment or NLRP3 silencing prevents CGI-58-deficient macrophages from over-secreting proinflammatory cytokines and from inducing proinflammatory signaling and IR in the co-cultured fat slices. Anti-ROS treatment also prevents exacerbation of inflammation and IR in HFD-fed MaKO mice. Our data thus establish CGI-58 as a suppressor of overnutrition-induced NLRP3 inflammasome activation in macrophages.

No abstract

The actin cytoskeleton is a dynamic cellular network known for its function in cell morphology and motility. Recent studies using high resolution and real time imaging techniques have revealed that actin plays a critical role in signal transduction, primarily by modulating the dynamics and organization of membrane-associated receptors and signaling molecules. This review summarizes what we have learned so far about a regulatory niche of the actin cytoskeleton in the signal transduction of the B cell receptor (BCR). The activation of the BCR is initiated and regulated by a close coordination between the dynamics of surface BCRs and the cortical actin network. The actin cytoskeleton is involved in regulating the signaling threshold of the BCR to antigenic stimulation, the kinetics and amplification of BCR signaling activities, and the timing and kinetics of signaling downregulation. Actin exerts its regulatory function by controlling the kinetics, magnitude, subcellular location, and nature of BCR clustering and BCR signaling complex formation at every stage of signaling. The cortical actin network is remodeled by initial detachment from the plasma membrane, disassembly and subsequent reassembly into new actin structures in response to antigenic stimulation. Signaling responsive actin regulators translate BCR stimulatory and inhibitory signals into a series of actin remodeling events, which enhance signaling activation and down-regulation by modulating the lateral mobility and spatial organization of surface BCR. The mechanistic understanding of actinmediated signaling regulation in B cells will help us explore B cell-specific manipulations of the actin cytoskeleton as treatments for B cell-mediated autoimmunity and B cell cancer. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters.

B-cell activation plays a crucial part in the immune system and is initiated via interaction between the B cell receptor (BCR) and specific antigens. In recent years with the help of modern imaging techniques, it was found that the cortical actin cytoskeleton changes dramatically during B-cell activation. In this review, we discuss how actin-cytoskeleton reorganization regulates BCR signaling in different stages of B-cell activation, specifically when stimulated by antigens, and also how this reorganization is mediated by BCR signaling molecules. Abnormal BCR signaling is associated with the progression of lymphoma and immunological diseases including autoimmune disorders, and recent studies have proved that impaired actin cytoskeleton can devastate the normal activation of B cells. Therefore, to figure out the coordination between the actin cytoskeleton and BCR signaling may reveal an underlying mechanism of B-cell activation, which has potential for new treatments for B-cell associated diseases.