bims-stacyt 2018-09-16 papers

Am J Reprod Immunol. 2018 Sep 08. e13045

Modulation of trophoblast function by concurrent hyperglycemia and antiphospholipid antibodies is in part TLR4-dependent.

Daisy Leon-Martinez, Melissa J Mulla, Christina S Han, Lawrence W Chamley, Vikki M Abrahams.

PROBLEM: While diabetes and APS are individually associated with increased risk of poor perinatal outcomes, in particular preeclampsia, recent studies have demonstrated an association between concurrent aPL and diabetes leading to an increased risk of pregnancy morbidity. Hyperglycemia and aPL have independently been shown to alter human trophoblast function by inducing a pro-inflammatory, anti-angiogenic, and antimigratory response. However, little is known about the effects of concurrent hyperglycemia and aPL on trophoblast function.METHOD OF STUDY: A human first-trimester extravillous trophoblast cell line was exposed to glucose at 5 mmol/L (normoglycemia) or 25 mmol/L (hyperglycemia), all in the presence or absence of low-dose aPL or control IgG. For some experiments, the TLR4 antagonist, LPS-RS, was included. Cell culture supernatants were measured for inflammatory IL-1β and IL-8, and angiogenic PlGF, sFlt-1, and sEndoglin by ELISA. Inflammasome-associated uric acid was measured using a bioassay; caspase-1 was measured using an activity assay. Trophoblast migration was quantified using a two-chamber colorimetric assay.
RESULTS: Compared to excess glucose alone, combination excess glucose and low-dose aPL (a) further augmented trophoblast inflammatory IL-1β, inflammasome-associated uric acid and caspase-1, and pro-angiogenic PlGF; (b) dampened trophoblast inflammatory IL-8, anti-angiogenic sEndoglin, and sFlt-1; and (c) further reduced trophoblast migration.
CONCLUSION: Our findings indicate that while concurrent aPL and hyperglycemia are overall detrimental to trophoblast function, the presence of two simultaneous insults triggers some protective effects.

Keywords: Toll-like receptor 4; antiphospholipid antibody; antiphospholipid syndrome; diabetes; hyperglycemia; preeclampsia; trophoblast

DOI: https://doi.org/10.1111/aji.13045

Brain Behav Immun. 2018 Sep 05. pii: S0889-1591(18)30544-0. [Epub ahead of print]

Evidence that NLRC4 Inflammasome Mediates Apoptotic and Pyroptotic Microglial Death Following Ischemic Stroke.

Luting Poh, Sung-Wook Kang, Sang-Ha Baik, Gavin Yong Quan Ng, David T She, Priyanka Balaganapathy, S Thameem Dheen, Tim Magnus, Mathias Gelderblom, Christopher G Sobey, Edward H Koo, David Y Fann, Thiruma V Arumugam.

Stroke is the second leading cause of death in the world and a major cause of long-term disability. Recent evidence has provided insight into a newly described inflammatory mechanism that contributes to neuronal and glial cell death, and impaired neurological outcome following ischemic stroke - a form of sterile inflammation involving innate immune complexes termed inflammasomes. It has been established that inflammasome activation following ischemic stroke contributes to neuronal cell death, but little is known about inflammasome function and cell death in activated microglial cells following cerebral ischemia. Microglia are considered the resident immune cells that function as the primary immune defense in the brain. This study has comprehensively investigated the expression and activation of NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes in isolates of microglial cells subjected to simulated ischemic conditions and in the brain following ischemic stroke. Immunoblot analysis from culture media indicated microglial cells release inflammasome components and inflammasome activation-dependent pro-inflammatory cytokines following ischemic conditions. In addition, a functional role for NLRC4 inflammasomes was determined using siRNA knockdown of NLRC4 and pharmacological inhibitors of caspase-1 and -8 to target apoptotic and pyroptotic cell death in BV2 microglial cells under ischemic conditions. In summary, the present study provides evidence that the NLRC4 inflammasome complex mediates the inflammatory response, as well as apoptotic and pyroptotic cell death in microglial cells under in vitro and in vivo ischemic conditions.

Keywords: Apoptosis; Cell Death; Inflammasomes; Inflammation; Ischemic Stroke; Microglia; NLRC4; Pyroptosis

DOI: https://doi.org/10.1016/j.bbi.2018.09.001

Mol Ther. 2018 Aug 16. pii: S1525-0016(18)30382-4. [Epub ahead of print]

PDGF Restores the Defective Phenotype of Adipose-Derived Mesenchymal Stromal Cells from Diabetic Patients.

Vivian Capilla-González, Javier López-Beas, Natalia Escacena, Yolanda Aguilera, Antonio de la Cuesta, Rafael Ruiz-Salmerón, Franz Martín, Abdelkrim Hmadcha, Bernat Soria.

Diabetes is a chronic metabolic disorder that affects 415 million people worldwide. This pathology is often associated with long-term complications, such as critical limb ischemia (CLI), which increases the risk of limb loss and mortality. Mesenchymal stromal cells (MSCs) represent a promising option for the treatment of diabetes complications. Although MSCs are widely used in autologous cell-based therapy, their effects may be influenced by the constant crosstalk between the graft and the host, which could affect the MSC fate potential. In this context, we previously reported that MSCs derived from diabetic patients with CLI have a defective phenotype that manifests as reduced fibrinolytic activity, thereby enhancing the thrombotic risk and compromising patient safety. Here, we found that MSCs derived from diabetic patients with CLI not only exhibit a prothrombotic profile but also have altered multi-differentiation potential, reduced proliferation, and inhibited migration and homing to sites of inflammation. We further demonstrated that this aberrant cell phenotype is reversed by the platelet-derived growth factor (PDGF) BB, indicating that PDGF signaling is a key regulator of MSC functionality. These findings provide an attractive approach to improve the therapeutic efficacy of MSCs in autologous therapy for diabetic patients.

Keywords: PDGF; adipose-derived mesenchymal stromal cells; critical limb ischemia; diabetes; homing; migration; proliferation; thrombotic state

DOI: https://doi.org/10.1016/j.ymthe.2018.08.011