TICAM-1/TRIF associates with Act1 and suppresses IL-17 receptor–mediated inflammatory responses

TICAM-1 (also called TRIF) is the sole adaptor of TLR3 that recognizes double-stranded RNA. Here, we report that TICAM-1 is involved not only in TLR3 signaling but also in the cytokine receptor IL-17RA signaling. We found that TICAM-1 bound to IL-17R adaptor Act1 to inhibit the interaction between IL-17RA and Act1. Interestingly, TICAM-1 knockout promoted IL-17RA/Act1 interaction and increased IL-17A–mediated activation of NF-κB and MAP kinases, leading to enhanced expression of inflammatory cytokines and chemokines upon IL-17A stimulation. Moreover, Ticam-1 knockout augmented IL-17A–mediated CXCL1 and CXCL2 expression in vivo, resulting in accumulation of myeloid cells. Furthermore, Ticam-1 knockout enhanced delayed type hypersensitivity and exacerbated experimental autoimmune encephalomyelitis. Ticam-1 knockout promoted accumulation of myeloid and lymphoid cells in the spinal cord of EAE-induced mice. Collectively, these data indicate that TICAM-1 inhibits the interaction between IL-17RA and Act1 and functions as a negative regulator in IL-17A–mediated inflammatory responses

Adaptation of the difficulty level in an infant-robot movement contingency study

19th International Workshop of Physical Agents (WAF). Madrid (22-23 Noviembre 2018)ABSTRACT: This paper presents a personalized contingency feedback adaptation system that aims to encourage infants aged 6 to 8 months to gradually increase the peak acceleration of their leg movements. The ultimate challenge is to determine if a socially assistive humanoid robot can guide infant learning using contingent rewards, where the reward threshold is personalized for each infant using a reinforcement learning algorithm. The model learned from the data captured by wearable inertial sensors measuring infant leg movement accelerations in an earlier study. Each infant generated a unique model that determined the behavior of the robot. The presented results were obtained from the distributions of the participants' acceleration peaks and demonstrate that the resulting model is sensitive to the degree of differentiation among the participants; each participant (infant) should have his/her own learned policy.This work was supported by NSF award 1706964 (PI: Smith, Co-PI: Matarić). In addition, this work was developed during an international mobility program at the University of Southern California being also partially funded by the European Union ECHORD++ project (FP7-ICT-601116), the LifeBots project (TIN2015-65686-C5) and THERAPIST project (TIN2012-38079)

Extracellular Vesicles Deliver Host and Virus RNA and Regulate Innate Immune Response

The innate immune system plays a crucial role in controlling viral infection. Pattern recognition receptors (PRRs), such as Toll-like receptors and RIG-I-like receptors, sense viral components called pathogen-associated molecular patterns (PAMPs) and trigger signals to induce innate immune responses. Extracellular vesicles (EVs), including exosomes and microvesicles, deliver functional RNA and mediate intercellular communications. Recent studies have revealed that EVs released from virus-infected cells deliver viral RNA to dendritic cells and macrophages, thereby activating PRRs in recipient cells, which results in the expression of type I interferon and pro-inflammatory cytokines. On the other hand, EVs transfer not only viral RNA but also host microRNAs to recipient cells. Recently, infection of hepatocytes with hepatitis B virus (HBV) was shown to affect microRNA levels in EVs released from virus-infected cells, leading to attenuation of host innate immune response. This suggests that the virus utilizes the EVs and host microRNAs to counteract the antiviral innate immune responses. In this review, we summarize recent findings related to the role of EVs in antiviral innate immune responses

Regulation of RIG-I Activation by K63-Linked Polyubiquitination

RIG-I is a pattern recognition receptor and recognizes cytoplasmic viral double-stranded RNA (dsRNA). Influenza A virus, hepatitis C virus, and several other pathogenic viruses are mainly recognized by RIG-I, resulting in the activation of the innate immune responses. The protein comprises N-terminal two caspase activation and recruitment domains (2CARDs), an RNA helicase domain, and the C-terminal domain (CTD). The CTD recognizes 5′-triphosphate viral dsRNA. After recognition of viral dsRNA, the protein harbors K63-linked polyubiquitination essential for RIG-I activation. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. MAVS aggregation then triggers the signal to induce the innate immune responses. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. MEX3C and TRIM4 mediate polyubiquitination of the 2CARDs. By contrast, Riplet ubiquitinates the CTD. The physiological significance of each ubiquitin ligases has been shown by knockout and knockdown studies, but there appears to be contradictory to evidence reported in the literature. In this review, we summarize recent findings related to K63-linked polyubiquitination and propose a model that could reconcile current contradictory theories. We also discuss the physiological significance of the ubiquitin ligases in the immune system against viral infection

Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g

Marked improvements have been achieved in the survival of extremely low birth weight infants, but survival rates and prognoses of extremely small infants with birth weights ≤500 g remain poor. The aim of this study was to clarify long-term outcomes for surviving infants with birth weights ≤500 g. Methods: The study population comprised fetuses of gestational age ≥22 weeks, expected live- or stillbirth weight ≤500 g, and birth date between 2003 and 2012. Developmental assessments were performed prospectively at 3 years old. Results: Data were obtained for 21 fetuses, including 10 live births and 11 stillbirths. Of the 10 live births, median gestational age was 25.2 weeks (range, 22.4–27.1 weeks), median birth weight was 426 g (range, 370–483 g), and two neonates died before discharge. One infant with severe asphyxia died within 12 h and another infant with Down syndrome died at 34 days. The survival rate was thus 80%. All surviving infants were small for gestational age. Seven of the 8 surviving infants (88%) weighed less than 2500 g at a corrected age of 40 weeks. Seven infants were available for developmental assessments at 3 years old. One infant could not be followed. Two of those seven infants (29%) showed normal development, three infants (42%) showed mild neurodevelopmental disability, and two infants (29%) showed severe neurodevelopmental disability. One infant had periventricular leukomalacia and cerebral palsy. Two of the seven infants (29%) had short stature (<3 SD) at 3 years old. Conclusion: Although the survival rate among live births was good (80%) in this study, neurodevelopmental outcomes remained poor in infants with birth weights ≤500 g. Further large studies are needed to assess long-term outcomes for extremely small infants

Immune-regulatory microRNA expression levels within circulating extracellular vesicles correspond with the appearance of local symptoms after seasonal flu vaccination.

Extracellular vesicles (EVs) contain microRNAs (miRNAs) that regulate the innate immune responses, such as the production of pro-inflammatory cytokines. The excessive production of pro-inflammatory cytokines after vaccination can cause local adverse reactions, such as pain, itching, swelling, and redness. Previous studies have shown that circulating EV miR-451a regulates innate immune responses, and miR-451a levels in serum EVs are negatively correlated with the pro-inflammatory cytokine expression levels in response to the influenza vaccine. Since excessive pro-inflammatory cytokine production is a cause of the local adverse reactions to vaccination, we investigated whether miR-451a levels in serum EVs correlate with local symptoms at the vaccination site, such as pain, itching, swelling, and redness. Interestingly, miR-451a levels in serum EVs were inversely correlated with the number of symptoms after vaccination. We determined the level of several other immune-regulatory miRNAs in serum EVs. Using the immune-regulatory miRNA levels of miR-22, miR-29a, miR-451a, and miR-107, we calculated a normalized miRNA level for each healthy donor and found that the normalized miRNA levels were significantly correlated with the number of local symptoms after vaccination. Our data indicated that immune-regulatory miRNA levels in serum EVs can be used as biomarkers to assess local symptoms after influenza vaccination

Zyxin stabilizes RIG-I and MAVS interactions and promotes type I interferon response

Abstract RIG-I and MDA5 are cytoplasmic viral RNA sensors that belong to the RIG-I-like receptors (RLRs), which induce antiviral innate immune responses, including the production of type I interferon and other pro-inflammatory cytokines. After recognition of viral RNA, the N-terminal caspase activation and recruitment domains (CARDs) of RIG-I and MDA5 bind to a CARD in the MAVS adaptor molecule, resulting in MAVS oligomerization and downstream signaling. To reveal the molecular mechanism of MAVS-dependent signaling, we performed a yeast two-hybrid screening and identified zyxin as a protein that binds to MAVS. Zyxin co-immunoprecipitated with MAVS in human cells. A proximity ligation assay showed that zyxin and MAVS partly co-localized on mitochondria. Ectopic expression of zyxin augmented MAVS-mediated IFN-β promoter activation, and knockdown of zyxin (ZYX) attenuated the IFN-β promoter activation. Moreover, ZYX knockdown reduced the expression of type I IFN and an interferon-inducible gene after stimulation with polyI:C or influenza A virus RNA. Interestingly, physical interactions between RLRs and MAVS were abrogated by ZYX knockdown. These observations indicate that zyxin serves as a scaffold for the interactions between RLRs and MAVS