Acarbose has sex-dependent and independent effects on age-related physical function, cardiac health and lipid biology

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Abstract

With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat Type 2 diabetes (T2DM) can extend mouse lifespan, with greater effect in males than in females. Utilizing a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological and biochemical changes that occur during aging, and determined which of the effects of age and drug were sex-dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving balance/coordination on an accelerating rotarod, rotarod endurance, and grip strength. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth promoting pathways and increased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids – changes which have previously been associated with aging, cardiac dysfunction and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride (TAG) accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging anti-aging effects in multiple tissues, and may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.

Authors

Jonathan J Herrera, Sean Louzon, Kaitlyn Pifer, Danielle Leander, Gennifer E. Merrihew, Jea H. Park, Kate Szczesniak, Jeremy A. Whitson, John E. Wilkinson, Oliver Fiehn, Michael J. MacCoss, Sharlene M. Day, Richard A. Miller, Michael Garratt

Assessment of HIV-1 integration in tissues and subsets across infection stages

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Abstract

The integration of HIV DNA into the host genome contributes to lifelong infection in most individuals. Few studies have examined integration in lymphoid tissue, where HIV predominantly persists before and after antiretroviral treatment (ART). Of particular interest is whether integration site distributions differ between infection stages with paired blood and tissue comparisons. Here, we profiled HIV integration site distributions in sorted memory, tissue resident, and/or follicular helper CD4+ T-cell subsets from paired blood and lymphoid tissue samples from acute, chronic, and ART-treated individuals (n=3 each). We observed minor differences in the frequency of non-intronic and non-distal intergenic sites varying with tissue and residency phenotypes during ART. Genomic and epigenetic annotations were generally similar. Clonal expansion of cells marked by identical integration sites was detected, with increased detection in chronic and ART-treated individuals. However, overlap between or within CD4+ T-cell subsets or tissue compartments was only observed in 8 unique sites out of 3,540 sites studied. Together, these findings suggest that shared integration sites between blood and tissue may, depending on the tissue site, be the exception rather than the rule, and indicate that additional studies are necessary to fully understand the heterogeneity of tissue sequestered HIV reservoirs.

Authors

Vincent H. Wu, Christopher L Nobles, Leticia Kuri-Cervantes, Kevin McCormick, John K. Everett, Son Nguyen, Perla M. del Río Estrada, Mauricio González-Navarro, Santiago Ávila-Ríos, Gustavo Reyes-Terán, Frederic D. Bushman, Michael R. Betts

Single-cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection

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Abstract

Myeloid cells are increasingly recognized as a major player in transplant rejection. Here, we used a murine kidney transplantation model and single-cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques including machine learning, we demonstrated that kidney allograft-infiltrating myeloid cells followed a trajectory of differentiating from monocytes to pro-inflammatory macrophages, and exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was Axl, a member of the receptor tyrosine kinase family TAM (Tyro3/Axl/Mertk). Using kidney transplant recipients with Axl gene deficiency, we further demonstrated that Axl augmented intragraft differentiation of pro-inflammatory macrophages, likely via its effect on the transcription factor Cebpb. This in turn promoted intragraft recruitment, differentiation and proliferation of donor-specific T cells, and enhanced early allograft inflammation evidenced by histology. We conclude that myeloid cell Axl expression identified by single-cell transcriptomics of kidney allografts in our study plays a major role in promoting intragraft myeloid cell and T cell differentiation, and presents a novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.

Authors

Anil Dangi, Naveen R. Natesh, Irma Husain, Zhicheng Ji, Laura Barisoni, Jean Kwun, Xiling Shen, Edward B. Thorp, Xunrong Luo

Serum amyloid A-containing HDL binds adipocyte-derived versican and macrophage-derived biglycan, reducing its anti-inflammatory properties

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Abstract

The ability of HDL to inhibit inflammation in adipocytes and adipose tissue is reduced when HDL contains serum amyloid A (SAA) due to trapping of SAA in HDL by proteoglycans at the adipocyte surface. Since we recently found that the major extracellular matrix proteoglycan produced by hypertrophic adipocytes is versican, whereas activated adipose tissue macrophages produce mainly biglycan, the role of proteoglycans in determining the anti-inflammatory properties of HDL was further investigated. The distribution of versican, biglycan, apolipoprotein A-I (the major apolipoprotein of HDL) and SAA were similar in adipose tissue from obese mice and obese human subjects. Co-localization of SAA-enriched HDL with versican and biglycan at the cell surface of adipocyte and peritoneal macrophages, respectively, was blocked by silencing these proteoglycans, which also restored the anti-inflammatory property of SAA-enriched HDL despite the presence of SAA. Similar to adipocytes, normal HDL exerts its anti-inflammatory function in macrophages by reducing lipid rafts, reactive oxygen species generation and translocation of toll like receptor 4 and NADPH oxidase 2 into lipid rafts, effects that are not observed with SAA-enriched HDL. These findings imply that SAA present in HDL can be trapped by adipocyte-derived versican and macrophage-derived biglycan, thereby blunting HDL’s anti-inflammatory properties.

Authors

Chang Yeop Han, Inkyung Kang, Mohamed Omer, Shari Wang, Tomasz Wietecha, Thomas N. Wight, Alan Chait

Dysregulation of tryptophan catabolism at the host-skin microbiota interface in Hidradenitis Suppurativa

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Abstract

Hidradenitis Suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway (KP) of tryptophan catabolism in dermal fibroblasts correlating with the release of KP-inducing cytokines by inflammatory cell infiltrates. Notably, over-activation of the KP in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the Aryl Hydrocarbon Receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in HS patients, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.

Authors

Laure Guenin-Macé, Jean-David Morel, Jean-Marc Doisne, Angèle Schiavo, Lysiane Boulet, Véronique Mayau, Pedro Goncalves, Sabine Duchatelet, Alain Hovnanian, Vincent Bondet, Darragh Duffy, Marie-Noëlle Ungeheuer, Maïa Delage, Aude Nassif, James P. Di Santo, Caroline Demangel

Inhibition of TRPV1 by SHP-1 in nociceptive primary sensory neurons is critical in PD-L1 analgesia

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Abstract

Recently programmed death-ligand 1 (PD-L1) receptor PD-1 was found in dorsal root ganglion (DRG) neurons, and PD-L1 activates PD-1 to inhibit inflammatory and neuropathic pain by modulating neuronal excitability. However, the downstream signaling of PD-1 in sensory neurons remains unclear. Here, we show that PD-L1 activates Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1) to downregulate transient receptor potential vanilloid 1 (TRPV1) in DRG neurons and inhibit bone cancer pain in mice. Local injection of PD-L1 produced analgesia. PD-1 in DRG neurons colocalized with TRPV1 and SHP-1. PD-L1 induced the phosphorylation of SHP-1 in DRG TRPV1 neurons and inhibited TRPV1 currents. Loss of TRPV1 in mice abolished bone cancer-induced thermal hyperalgesia and PD-L1 analgesia. Conditioned deletion of SHP-1 in NaV1.8+ neurons aggravated bone cancer pain and diminished the inhibition of PD-L1 on TRPV1 currents and pain. Together, our findings suggest that PD-L1/PD1 signaling suppress bone cancer pain via inhibition of TRPV1 activity. Our results also suggest that SHP-1 in sensory neurons is an endogenous pain inhibitor and delayed the development of bone cancer pain via suppressing TRPV1 function.

Authors

Ben-Long Liu, Qi-Lai Cao, Xin Zhao, Hui-Zhu Liu, Yu-Qiu Zhang

Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling

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Abstract

Schwannomas are tumors of the Schwann cells that cause chronic pain, numbness, and potentially life-threatening impairment of vital organs. Despite the identification of causative genes including NF2 (Merlin), INI1/SMARCB1, and LZTR1, the exact molecular mechanism of schwannoma development is still poorly understood. Several studies have identified Merlin as a key regulator of the Hippo, MAPK, and PI3K signaling pathways, however definitive evidence demonstrating the importance of these pathways in schwannoma pathogenesis is absent. Here, we provide direct genetic evidence that dysregulation of the Hippo pathway in the Schwann cell lineage causes development of multiple Schwannomas in mice. We found that canonical Hippo signaling through the effectors YAP/TAZ is required for schwannomagenesis and that MAPK signaling modifies schwannoma formation. Furthermore, co-targeting YAP/TAZ transcriptional activity and MAPK signaling demonstrated a synergistic therapeutic effect on schwannoma. Our new model provides a tractable platform to dissect the molecular mechanisms underpinning schwannoma formation and the role of combinatorial targeted therapy in schwannoma treatment.

Authors

Zhiguo Chen, Stephen Li, Juan Mo, Eric T. Hawley, Yong Wang, Yongzheng He, Jean-Philippe Brosseau, Tracey Shipman, D. Wade Clapp, Thomas J. Carroll, Lu Q. Le

ROS producing immature neutrophils in Giant Cell Arteritis are linked to vascular pathologies

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Abstract

Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b+CD15+CD10lo/-CD64- band neutrophils and CD66bhiCD15+CD10lo/-CD64+/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro co-culture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a new clinical cellular signature of GCA and suggesting new therapeutic approaches in systemic vascular inflammation.

Authors

Lihui Wang, Zhichao Ai, Tariq E. Khoyratty, Kristina Zec, Hayley L. Eames, Erinke van Grinsven, Alison Hudak, Susan Morris, David J. Ahern, Claudia Monaco, Evgeniy B. Eruslanov, Raashid Luqmani, Irina A. Udalova

Renal proximal tubular NEMO plays a critical role in ischemic acute kidney injury

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Abstract

We determined that renal proximal tubular (PT) NFκB essential modulator (NEMO) plays a direct and critical role in ischemic acute kidney injury (AKI) utilizing using mice lacking renal PT NEMO and by targeted renal PT NEMO inhibition with mesoscale nanoparticle encapsulated NEMO binding peptide (MNP NBP). We subjected renal PT NEMO deficient mice, wild type (WT) mice and C57BL/6 mice to sham surgery or 30 min renal ischemia and reperfusion (IR). C57BL/6 mice received NBP MNP or empty MNP before renal IR injury. Mice treated with MNP NBP and mice deficient in renal PT NEMO were protected against ischemic AKI with decreased renal tubular necrosis, inflammation and apoptosis compared to control MNP treated or WT mice, respectively. Recombinant peptidylarginine deiminase type-4 (rPAD4) targets kidney PT NEMO to exacerbate ischemic AKI as exogenous rPAD4 exacerbated renal IR injury in WT mice but not in renal proximal tubule NEMO deficient mice. Furthermore, rPAD4 upregulated proinflammatory cytokine mRNA and NFκB activation in freshly isolated renal proximal tubules from WT mice but not from PT NEMO deficient mice. Taken together, our studies suggest that renal PT NEMO plays a critical role in ischemic AKI by promoting renal tubular inflammation, apoptosis as well as necrosis.

Authors

Sang Jun Han, Ryan M. williams, Mihwa Kim, Daniel A. Heller, Vivette D'Agati, Marc Schmidt-Supprian, H. Thomas Lee

Selective inhibition of arginase-2 in endothelial cells but not proximal tubules reduces renal fibrosis

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Abstract

Fibrosis is the final common pathway in the pathophysiology of most forms of chronic kidney disease (CKD). As treatment of renal fibrosis still remains largely supportive, a refined understanding of the cellular and molecular mechanisms of kidney fibrosis and the development of novel compounds are urgently needed. Whether arginases play a role in development of fibrosis in CKD is unclear. We hypothesize that endothelial-arginase-2 (Arg2) promotes the development of kidney fibrosis induced by unilateral ureteral obstruction (UUO). Arg2 expression and arginase activity significantly increased following renal fibrosis. Pharmacological blockade or genetic deficiency of Arg2 conferred kidney protection following renal fibrosis as reflected by a reduction in kidney interstitial fibrosis and fibrotic markers. Selective deletion of Arg2 in endothelial cells (Tie2Cre/Arg2flox/flox) reduced the level of fibrosis after UUO. In contrast, selective deletion of Arg2 specifically in proximal tubular cells (Ggt1Cre/Arg2flox/flox) failed to reduce renal fibrosis after UUO. Furthermore, arginase inhibition restored kidney nitric oxide (NO) levels, oxidative stress, and mitochondrial function following UUO.These findings indicate that endothelial-Arg2 plays a major role in renal fibrosis via its action on NO and mitochondrial function. Blocking Arg2 activity or expression could be a novel therapeutic approach for prevention of CKD.

Authors

Michael Wetzel, Kristen Stanley, Wei Wei Wang, Soumya Maity, Muniswamy Madesh, W. Brian Reeves, Alaa S. Awad