Citations 2
Activation of FAK/Rac1/Cdc42‐GTPase signaling ameliorates impaired microglial migration response to Aβ 42 in triggering receptor expressed on myeloid cells 2 loss‐of‐function murine models
Rong, Zhouyi , Cheng, Baoying, Zhong, Li , Jia, Lin , Li, Yanfang , Shue, Francis , Wang, Na , Cheng, Yiyun , Huang, Xiaohua , Liu, Chia‐Chen , Fryer, John Denis , Wang, Xin , Zhang, Yun‐wu , Zheng, Honghua , Liu, Chia-Chen , Shue, Francis , Ye, Xiaowen , Li, Xin , Wang, Na
The FASEB Journal | July 29, 2020 | Volume: 34 | Issue: 8 | Pages: 10984-10997
Abstract Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid‐β (Aβ) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2‐regulated microglia recruitment to Aβ plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2 −/− mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD‐associated R47H mutation results in inhibition of FAK and Rac1/Cdc42‐GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42‐GTPase activator, partially enhances microglial migration in response to oligomeric Aβ 42 in Trem2 −/− or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD‐associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aβ 42 , suggesting a therapeutic target for R47H‐bearing patients with high risk of AD.
Absence of VEGFR‐1/Flt‐1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model
Qiu, Sujun , Shi, Changgui , Anbazhagan, Arivarasu Natarajan , Das, Vaskar, Arora, Vipin , Kc, Ranjan , O‐Sullivan, InSug , Wijnen, André J. van , Chintharlapalli, Sudhakar , Gott‐Velis, Gina, Richard, Ripper, Mwale, Fackson , Shibuya, Masabumi , Min, Shaoxiong , Im, Hee‐Jeong , van Wijnen, Andre J , Li, Xin
Journal of Cellular Physiology | December 25, 2019 | Volume: 235 | Issue: 6 | Pages: 5305-5317
Abstract Although degenerative disc disease (DDD) and related low back pain (LBP) are growing public health problems, the underlying disease mechanisms remain unclear. An increase in the vascular endothelial growth factor (VEGF) levels in DDD has been reported. This study aimed to examine the role of VEGF receptors (VEGFRs) in DDD, using a mouse model of DDD. Progressive DDD was induced by anterior stabbing of lumbar intervertebral discs in wild type (WT) and VEGFR‐1 tyrosine‐kinase deficient mice ( vegfr‐1 TK−/ − ). Pain assessments were performed weekly for 12 weeks. Histological and immunohistochemical assessments were made for discs, dorsal root ganglions, and spinal cord. Both vegfr‐1 TK − / − and WT mice presented with similar pathological changes in discs with an increased expression of inflammatory cytokines and matrix‐degrading enzymes. Despite the similar pathological patterns, vegfr‐1 TK − / − mice showed insensitivity to pain compared with WT mice. This insensitivity to discogenic pain was related to lower levels of pain factors in the discs and peripheral sensory neurons and lower spinal glial activation in the vegfr‐1 TK − / − mice than in the WT mice. Exogenous stimulation of bovine disc cells with VEGF increased inflammatory and cartilage degrading enzyme. Silencing vegfr‐1 by small‐interfering‐RNA decreased VEGF‐induced expression of pain markers, while silencing vegfr‐2 decreased VEGF‐induced expression of inflammatory and metabolic markers without changing pain markers. This suggests the involvement of VEGFR‐1 signaling specifically in pain transmission. Collectively, our results indicate that the VEGF signaling is involved in DDD. Particularly, VEGFR‐1 is critical for discogenic LBP transmission independent of the degree of disc pathology.