Research
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI122530.
Abstract
Mast cells (MCs) are immune sentinels but whether they also function as antigen-presenting cells (APCs) remains elusive. Using mouse models of MC-deficiency, we report MC-dependent recruitment and activation of multiple T cell subsets to the skin and draining lymph nodes (LNs) during dengue virus (DENV) infection. Newly-recruited and locally-proliferating γδT cells were the first responding T cell subset to MC-driven inflammation and their production of IFN-γ was MC-dependent. MC-γδ T cell conjugates were observed consistently in infected peripheral tissues, suggesting a new role for MCs as non-conventional APCs for γδT cells. MC-dependent γδT cell activation and proliferation during DENV infection required TCR signaling and the non-conventional antigen presentation molecule EPCR on MCs. γδT cells, not previously implicated in DENV host defense, killed infected target dendritic cells and contributed to clearance of DENV in vivo. We believe immune synapse formation between MCs and γδT cells is a novel mechanism to induce specific and protective immunity at sites of viral infection.
Authors
Chinmay Kumar Mantri, Ashley L. St. John
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI121561.
Abstract
Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling in sensory innervation for OA pain. We show that osteoclasts secrete NETRIN1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, DRG neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for NETRIN1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase (TRAP) positive osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g. NETRIN1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.
Authors
Shouan Zhu, Jianxi Zhu, Gehua Zhen, Yihe Hu, Senbo An, Yusheng Li, Qin Zheng, Zhiyong Chen, Ya Yang, Mei Wan, Richard Leroy Skolasky, Yong Cao, Tianding Wu, Bo Gao, Mi Yang, Manman Gao, Julia Kuliwaba, Shuangfei Ni, Lei Wang, Chuanlong Wu, David Findlay, Holger K. Eltzschig, Hong Wei Ouyang, Janet Crane, Feng-Quan Zhou, Yun Guan, Xinzhong Dong, Xu Cao
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI123366.
Abstract
Both natural influenza infection and current seasonal influenza vaccines primarily induce neutralising antibody responses against highly diverse epitopes within the “head” of the viral hemagglutinin (HA) protein. There is increasing interest on redirecting immunity towards the more conserved HA-stem or stalk as a means to broaden protective antibody responses. Here we examined HA-stem-specific B cell and T-follicular helper (Tfh) cell responses in the context of influenza infection and immunisation in mouse and monkey models. We found that during infection the stem domain was immunologically subdominant to the head in terms of serum antibody production and antigen-specific B and Tfh responses. Similarly, we found HA-stem immunogens were poorly immunogenic compared to the full-length HA with abolished sialic acid binding activity, with limiting Tfh elicitation a potential constraint to the induction or boosting of anti-stem immunity by vaccination. Finally, we confirm that currently licensed seasonal influenza vaccines can boost pre-existing memory responses against the HA-stem in humans. An increased understanding of the immune dynamics surrounding the HA-stem is essential to inform the design of next-generation influenza vaccines for broad and durable protection.
Authors
Hyon-Xhi Tan, Sinthujan Jegaskanda, Jennifer A. Juno, Robyn Esterbauer, Julius Wong, Hannah G. Kelly, Yi Liu, Danielle Tilmanis, Aeron C. Hurt, Jonathan W. Yewdell, Stephen J. Kent, Adam K. Wheatley
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI120572.
Abstract
ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in two primary-antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal-zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients’ blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centres and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target ROCK, the patients’ lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in patients’ cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signalling, and confining B lymphocytes and myelocytes within their dedicated functional environment.
Authors
Amine Bouafia, Sébastien Lofek, Julie Bruneau, Loïc Chentout, Hicham Lamrini, Amélie Trinquand, Marie-Céline Deau, Lucie Heurtier, Véronique Meignin, Capucine Picard, Elizabeth Macintyre, Olivier Alibeu, Marc Bras, Thierry Jo Molina, Marina Cavazzana, Isabelle André-Schmutz, Anne Durandy, Alain Fischer, Eric Oksenhendler, Sven Kracker
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI122035.
Abstract
Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent upon the Atg-conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of Ulk1, Rab9, Rip1 and Drp1. This complex allowed recruitment of trans-Golgi membranes associated with Rab9 to damaged mitochondria through Ser179 phosphorylation of Rab9 by Ulk1 and Ser616 phosphorylation of Drp1 by Rip1. Knock-in of Rab9 (S179A) abolished mitophagy and exacerbated injury in response to myocardial ischemia without affecting conventional autophagy. Mitophagy mediated through the Ulk1-Rab9-Rip1-Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.
Authors
Toshiro Saito, Jihoon Nah, Shin-ichi Oka, Risa Mukai, Yoshiya Monden, Yusuhiro Maejima, Yoshiyuki Ikeda, Sebastiano Sciarretta, Tong Liu, Hong Li, Erdene Baljinnyam, Diego Fraidenraich, Luke Fritzky, Peiyong Zhai, Shizuko Ichinose, Mitsuaki Isobe, Chiao-Po Hsu, Mondira Kundu, Junichi Sadoshima
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI120606.
Abstract
Peroxisomes perform essential functions in lipid metabolism, including fatty acid oxidation and plasmalogen synthesis. Here, we describe a role for peroxisomal lipid metabolism in mitochondrial dynamics in brown and beige adipocytes. Adipose tissue peroxisomal biogenesis was induced in response to cold exposure through activation of the thermogenic co-regulator PRDM16. Adipose-specific knockout of the peroxisomal biogenesis factor Pex16 (Pex16-AKO) in mice impaired cold tolerance, decreased energy expenditure, and increased diet-induced obesity. Pex16 deficiency blocked cold-induced mitochondrial fission, decreased mitochondrial copy number, and caused mitochondrial dysfunction. Adipose-specific knockout of the peroxisomal beta-oxidation enzyme acyl CoA oxidase 1 (Acox1-AKO) was not sufficient to affect adiposity, thermogenesis or mitochondrial copy number, but knockdown of the plasmalogen synthetic enzyme glyceronephosphate O-acyltransferase (GNPAT) recapitulated the effects of Pex16 inactivation on mitochondrial morphology and function. Plasmalogens are present in mitochondria and decreased with Pex16 inactivation. Their dietary supplementation increased mitochondrial copy number, improved mitochondrial function, and rescued thermogenesis in Pex16-AKO mice. These findings support a surprising interaction between peroxisomes and mitochondria to regulate mitochondrial dynamics and thermogenesis.
Authors
Hongsuk Park, Anyuan He, Min Tan, Jordan M. Johnson, John M. Dean, Terri A. Pietka, Yali Chen, Xiangyu Zhang, Fong-Fu Hsu, Babak Razani, Katsuhiko Funai, Irfan J. Lodhi
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI122478.
Abstract
The adenomatous polyposis coli (APC) gene plays a pivotal role in the pathogenesis of colorectal carcinoma (CRC), but remains a challenge for drug development. Long non-coding RNAs (lncRNAs) are invaluable in identifying cancer pathologies, and providing therapeutic options for cancer patients. Here, we identified a lncRNA (lncRNA-APC1) activated by APC through lncRNA microarray screening, and examined its expression among a large cohort of CRC tissues. A decrease in lncRNA-APC1 expression was positively associated with lymph node and/or distant metastasis, a more advanced clinical stage, as well as a poor prognosis of CRC patients. Additionally, APC can enhance lncRNA-APC1 expression by suppressing the enrichment of PPARα on the lncRNA-APC1 promoter. Furthermore, enforced lncRNA-APC1 expression was sufficient to inhibit CRC cell growth, metastasis and tumor angiogenesis by suppressing exosome production through directly binding Rab5b mRNA and reducing its stability. Importantly, exosomes derived from lncRNA-APC1-silenced CRC cells promoted angiogenesis by activating the MAPK pathway in endothelial cells, and moreover, exosomal Wnt1 largely enhanced CRC cell proliferation and migration through non-canonicial Wnt signaling. Collectively, lncRNA-APC1 is a critical lncRNA regulated by APC in the pathogenesis of CRC. Our findings suggest an APC-regulated lncRNA-APC1 program as an exploitable therapeutic maneuver for CRC patients.
Authors
Feng-Wei Wang, Chen-Hui Cao, Kai Han, Yong-Xiang Zhao, Mu-Yan Cai, Zhi-Cheng Xiang, Jia-Xing Zhang, Jie-Wei Chen, Li-Ping Zhong, Yong Huang, Su-Fang Zhou, Xiao-Han Jin, Xin-Yuan Guan, Rui-Hua Xu, Dan Xie
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI122367.
Abstract
Prostate cancer (PCa) progressed to castration resistance (CRPC) is a fatal disease. CRPC tumors develop resistance to new-generation anti-androgen enzalutamide through lineage plasticity, characterized by epithelial-mesenchymal transition (EMT) and basal-like phenotype. FOXA1 is a transcription factor essential for epithelial lineage differentiation. Here, we demonstrate that FOXA1 loss leads to remarkable up-regulation of transforming growth factor beta 3 (TGFB3), which encodes a ligand of TGF-β pathway. Mechanistically, this is due to genomic occupancy of FOXA1 on an upstream enhancer of TGFB3 gene to directly inhibit its transcription. Functionally, FOXA1 down-regulation induces TGF-β signaling, EMT, and cell motility, which is effectively blocked by TGF-β receptor I inhibitor Galunisertib (LY2157299). Tissue microarray analysis confirmed reduced levels of FOXA1 protein and a concordant increase in TGF-β signaling, indicated by SMAD2 phosphorylation, in CRPC as compared to primary tumors. Importantly, combinatorial LY2157299 treatment sensitized PCa cells to enzalutamide, leading to synergistic effects in inhibiting cell invasion in vitro and xenograft CRPC tumor growth and metastasis in vivo. Therefore, our study establishes FOXA1 as an important regulator of lineage plasticity mediated in part by TGF-β signaling and supports a novel therapeutic strategy to control lineage switching and potentially extend clinical response to antiandrogen therapies.
Authors
Bing Song, Su-Hong Park, Jonathan C. Zhao, Ka-wing Fong, Shangze Li, Yongik Lee, Yeqing A. Yang, Subhasree Sridhar, Xiaodong Lu, Sarki A. Abdulkadir, Robert L. Vessella, Colm Morrissey, Timothy M. Kuzel, William J. Catalona, Ximing J. Yang, Jindan Yu
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI123557.
Abstract
Loss of phosphatase and tensin homolog (PTEN) represents one hallmark of prostate cancer (PCa). However, restoration of PTEN or inhibition of the activated PI3K-AKT pathway has shown limited success, prompting us to identify obligate targets for disease intervention. We hypothesized that PTEN loss might expose cells to unique epigenetic vulnerabilities. Here, we identified a synthetic lethal relationship between PTEN and BRG1, an ATPase subunit of the SWI/SNF chromatin remodeling complex. Higher BRG1 expression in tumors with low PTEN expression was associated with a worse clinical outcome. Genetically engineered mice (GEMs) and organoid assays confirmed that ablation of PTEN sensitized the cells to BRG1 depletion. Mechanistically, PTEN loss stabilized BRG1 protein through the inhibition of the AKT-GSK3β-FBXW7 axis. Increased BRG1 expression in PTEN-deficient PCa cells led to chromatin remodeling into configurations that drive a protumorigenic transcriptome, causing cells to become further addicted to BRG1. Furthermore, we showed in preclinical models that BRG1 antagonist selectively inhibited the progression of PTEN-deficient prostate tumors. Together, our results highlight the synthetic lethal relationship between PTEN and BRG1, and support targeting BRG1 as an effective approach to the treatment of PTEN-deficient PCa.
Authors
Yufeng Ding, Ni Li, Baijun Dong, Wangxin Guo, Hui Wei, Qilong Chen, Huairui Yuan, Ying Han, Hanwen Chang, Shan Kan, Xuege Wang, Qiang Pan, Ping Wu, Chao Peng, Tong Qiu, Qintong Li, Dong Gao, Wei Xue, Jun Qin
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI97631.
Abstract
Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double strand break (DSB) misrepair. Here we report single dose radiotherapy (SDRT), a disruptive technique that ablates >90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase (ASMase)-mediated microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction post-SDRT conferred an ischemic stress response within parenchymal tumor cells, with reactive oxygen species triggering the evolutionarily conserved SUMO Stress Response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensible for homology-directed repair (HDR) of DSBs, HDR loss-of-function post-SDRT yielded DSB unrepair, chromosomal aberrations and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging post-SDRT using peroxiredoxin-6 overexpression or the SOD-mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss-of-function and SDRT tumor ablation. We also provide evidence of mouse to human translation of this biology in a randomized clinical trial, showing 24Gy SDRT, but not 3x9Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing SDRT/ASMase signaling, as current studies indicate this pathway is tractable to pharmacologic intervention.
Authors
Sahra Bodo, Cecile Campagne, Tin Htwe Thin, Daniel S. Higginson, H. Alberto Vargas, Guoqiang Hua, John D. Fuller, Ellen Ackerstaff, James Russell, Zhigang Zhang, Stefan Klingler, HyungJoon Cho, Matthew G. Kaag, Yousef Mazaheri, Andreas Rimner, Katia Manova-Todorova, Boris Epel, Joan Zatcky, Cristian R. Cleary, Shyam S. Rao, Yoshiya Yamada, Michael J. Zelefsky, Howard J. Halpern, Jason A. Koutcher, Carlos Cordon-Cardo, Carlo Greco, Adriana Haimovitz-Friedman, Evis Sala, Simon N. Powell, Richard Kolesnick, Zvi Fuks
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Copyright © 2018 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)