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Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation

Antigen (Ag)-triggered B-cell receptor (BCR) signaling initiates antibody responses. However, prolonged or uncontrolled BCR signaling is associated with the development of self-reactive B-cells and autoimmune diseases. We previously showed that actin-mediated B-cell contraction on Ag-presenting surf...

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Autores principales: Seeley-Fallen, Margaret K., Lazzaro, Michelle, Liu, Chaohong, Li, Quan-Zhen, Upadhyaya, Arpita, Song, Wenxia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047714/
https://www.ncbi.nlm.nih.gov/pubmed/35493485
http://dx.doi.org/10.3389/fimmu.2022.842605
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author Seeley-Fallen, Margaret K.
Lazzaro, Michelle
Liu, Chaohong
Li, Quan-Zhen
Upadhyaya, Arpita
Song, Wenxia
author_facet Seeley-Fallen, Margaret K.
Lazzaro, Michelle
Liu, Chaohong
Li, Quan-Zhen
Upadhyaya, Arpita
Song, Wenxia
author_sort Seeley-Fallen, Margaret K.
collection PubMed
description Antigen (Ag)-triggered B-cell receptor (BCR) signaling initiates antibody responses. However, prolonged or uncontrolled BCR signaling is associated with the development of self-reactive B-cells and autoimmune diseases. We previously showed that actin-mediated B-cell contraction on Ag-presenting surfaces negatively regulates BCR signaling. Non-muscle myosin II (NMII), an actin motor, is involved in B-cell development and antibody responses by mediating B-cell migration, cytokinesis, and Ag extraction from Ag-presenting cells. However, whether and how NMII regulates humoral responses through BCR signaling remains elusive. Utilizing a B-cell-specific, partial NMIIA knockout (cIIAKO) mouse model and NMII inhibitors, this study examined the role of NMII in BCR signaling. Upon BCR binding to antibody-coated planar lipid bilayers (PLB), NMIIA was recruited to the B-cell contact membrane and formed a ring-like structure during B-cell contraction. NMII recruitment depended on phosphatidylinositol 5-phosphatase (SHIP1), an inhibitory signaling molecule. NMII inhibition by cIIAKO did not affect B-cell spreading on PLB but delayed B-cell contraction and altered BCR clustering. Surface BCR “cap” formation induced by soluble stimulation was enhanced in cIIAKO B-cells. Notably, NMII inhibition by cIIAKO and inhibitors up-regulated BCR signaling in response to both surface-associated and soluble stimulation, increasing phosphorylated tyrosine, CD79a, BLNK, and Erk and decreasing phosphorylated SHIP1. While cIIAKO did not affect B-cell development, the number of germinal center B-cells was significantly increased in unimmunized cIIAKO mice, compared to control mice. While cIIAKO mice mounted similar antibody responses when compared to control mice upon immunization, the percentages of high-affinity antibodies, Ag-specific germinal center B-cells and isotype switched B-cells were significantly lower in cIIAKO mice than in control mice. Furthermore, autoantibody levels were elevated in cIIAKO mice, compared to control mice. Collectively, our results reveal that NMII exerts a B-cell-intrinsic inhibition on BCR signaling by regulating B-cell membrane contraction and surface BCR clustering, which curtails the activation of non-specific and self-reactive B-cells.
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spelling pubmed-90477142022-04-29 Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation Seeley-Fallen, Margaret K. Lazzaro, Michelle Liu, Chaohong Li, Quan-Zhen Upadhyaya, Arpita Song, Wenxia Front Immunol Immunology Antigen (Ag)-triggered B-cell receptor (BCR) signaling initiates antibody responses. However, prolonged or uncontrolled BCR signaling is associated with the development of self-reactive B-cells and autoimmune diseases. We previously showed that actin-mediated B-cell contraction on Ag-presenting surfaces negatively regulates BCR signaling. Non-muscle myosin II (NMII), an actin motor, is involved in B-cell development and antibody responses by mediating B-cell migration, cytokinesis, and Ag extraction from Ag-presenting cells. However, whether and how NMII regulates humoral responses through BCR signaling remains elusive. Utilizing a B-cell-specific, partial NMIIA knockout (cIIAKO) mouse model and NMII inhibitors, this study examined the role of NMII in BCR signaling. Upon BCR binding to antibody-coated planar lipid bilayers (PLB), NMIIA was recruited to the B-cell contact membrane and formed a ring-like structure during B-cell contraction. NMII recruitment depended on phosphatidylinositol 5-phosphatase (SHIP1), an inhibitory signaling molecule. NMII inhibition by cIIAKO did not affect B-cell spreading on PLB but delayed B-cell contraction and altered BCR clustering. Surface BCR “cap” formation induced by soluble stimulation was enhanced in cIIAKO B-cells. Notably, NMII inhibition by cIIAKO and inhibitors up-regulated BCR signaling in response to both surface-associated and soluble stimulation, increasing phosphorylated tyrosine, CD79a, BLNK, and Erk and decreasing phosphorylated SHIP1. While cIIAKO did not affect B-cell development, the number of germinal center B-cells was significantly increased in unimmunized cIIAKO mice, compared to control mice. While cIIAKO mice mounted similar antibody responses when compared to control mice upon immunization, the percentages of high-affinity antibodies, Ag-specific germinal center B-cells and isotype switched B-cells were significantly lower in cIIAKO mice than in control mice. Furthermore, autoantibody levels were elevated in cIIAKO mice, compared to control mice. Collectively, our results reveal that NMII exerts a B-cell-intrinsic inhibition on BCR signaling by regulating B-cell membrane contraction and surface BCR clustering, which curtails the activation of non-specific and self-reactive B-cells. Frontiers Media S.A. 2022-04-14 /pmc/articles/PMC9047714/ /pubmed/35493485 http://dx.doi.org/10.3389/fimmu.2022.842605 Text en Copyright © 2022 Seeley-Fallen, Lazzaro, Liu, Li, Upadhyaya and Song https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Seeley-Fallen, Margaret K.
Lazzaro, Michelle
Liu, Chaohong
Li, Quan-Zhen
Upadhyaya, Arpita
Song, Wenxia
Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation
title Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation
title_full Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation
title_fullStr Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation
title_full_unstemmed Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation
title_short Non-Muscle Myosin II Is Essential for the Negative Regulation of B-Cell Receptor Signaling and B-Cell Activation
title_sort non-muscle myosin ii is essential for the negative regulation of b-cell receptor signaling and b-cell activation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047714/
https://www.ncbi.nlm.nih.gov/pubmed/35493485
http://dx.doi.org/10.3389/fimmu.2022.842605
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