TY - JOUR
T1 - Small molecule inhibition of Rab7 impairs B cell class switching and plasma cell survival to dampen the autoantibody response in murine lupus
AU - Lam, Tonika
AU - Kulp, Dennis V.
AU - Wang, Rui
AU - Lou, Zheng
AU - Taylor, Julia
AU - Rivera, Carlos E.
AU - Yan, Hui
AU - Zhang, Qi
AU - Wang, Zhonghua
AU - Zan, Hong
AU - Ivanov, Dmitri N.
AU - Zhong, Guangming
AU - Casali, Paolo
AU - Xu, Zhenming
N1 - Funding Information:
This work was supported by National Institutes of Health Grants AI 079705 and AI 105813 (to P.C.), AI 124172 (to Z.X.), AI 104476 (to D.N.I.), and AI 047997 (to G.Z.). P.C. was also partially supported by Alliance for Lupus Research Target Identification in Lupus Grant ALR 295955 and the Zachry Foundation Distinguished Chair, D.N.I. by a Voelcker Fund Young Investigator Award, H.Z. by an Arthritis National Research Foundation research grant, and R.W. by the Xiangya School of Medicine, Central South University of China.
Publisher Copyright:
© Copyright 2016 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. In this study, we showed that the classswitched IgG autoantibody response in MRL/Faslpr/lpr and C57/Sle1Sle2Sle2 mice was blocked by the CID 1067700 compound, which specifically targeted Ras-related in brain 7 (Rab7), an endosome-localized small GTPase that was upregulated in activated human and mouse lupus B cells, leading to prevention of disease development and extension of lifespan. These were associated with decreased IgG-expressing B cells and plasma cells, but unchanged numbers and functions of myeloid cells and T cells. The Rab7 inhibitor suppressed T cell-dependent and T cell-independent Ab responses, but it did not affect T cell-mediated clearance of Chlamydia infection, consistent with a B cell-specific role of Rab7. Indeed, B cells and plasma cells were inherently sensitive to Rab7 gene knockout or Rab7 activity inhibition in class switching and survival, respectively, whereas proliferation/survival of B cells and generation of plasma cells were not affected. Impairment of NF-κB activation upon Rab7 inhibition, together with the rescue of B cell class switching and plasma cell survival by enforced NF-κB activation, indicated that Rab7 mediates these processes by promoting NF-κB activation, likely through signal transduction on intracellular membrane structures. Thus, a single Rab7-inhibiting small molecule can target two stages of B cell differentiation to dampen the pathogenic autoantibody response in lupus.
AB - IgG autoantibodies mediate pathology in systemic lupus patients and lupus-prone mice. In this study, we showed that the classswitched IgG autoantibody response in MRL/Faslpr/lpr and C57/Sle1Sle2Sle2 mice was blocked by the CID 1067700 compound, which specifically targeted Ras-related in brain 7 (Rab7), an endosome-localized small GTPase that was upregulated in activated human and mouse lupus B cells, leading to prevention of disease development and extension of lifespan. These were associated with decreased IgG-expressing B cells and plasma cells, but unchanged numbers and functions of myeloid cells and T cells. The Rab7 inhibitor suppressed T cell-dependent and T cell-independent Ab responses, but it did not affect T cell-mediated clearance of Chlamydia infection, consistent with a B cell-specific role of Rab7. Indeed, B cells and plasma cells were inherently sensitive to Rab7 gene knockout or Rab7 activity inhibition in class switching and survival, respectively, whereas proliferation/survival of B cells and generation of plasma cells were not affected. Impairment of NF-κB activation upon Rab7 inhibition, together with the rescue of B cell class switching and plasma cell survival by enforced NF-κB activation, indicated that Rab7 mediates these processes by promoting NF-κB activation, likely through signal transduction on intracellular membrane structures. Thus, a single Rab7-inhibiting small molecule can target two stages of B cell differentiation to dampen the pathogenic autoantibody response in lupus.
UR - http://www.scopus.com/inward/record.url?scp=84994474380&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994474380&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1601427
DO - 10.4049/jimmunol.1601427
M3 - Article
C2 - 27742832
AN - SCOPUS:84994474380
SN - 0022-1767
VL - 197
SP - 3792
EP - 3805
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -