TLRs are important pattern-recognition receptors involved in the activation of innate immune responses against foreign pathogens. TLR10 is the only TLR family member without a known ligand, signaling pathway, or clear cellular function. Previous work has shown that TLR10 suppresses proinflammatory cytokine production in response to TLR agonists in a mixed human mononuclear cell population. We report that TLR10 is preferentially expressed on monocytes and suppresses proinflammatory cytokine production resulting from either TLR or CD40 stimulation. TLR10 engagement affects both the MAPK and Akt signaling pathways, leading to changes in the transcriptome of isolated human monocytes. Differentiation of monocytes into dendritic cells in the presence of an αTLR10 mAb reduced the expression of maturation markers and the induction of proinflammatory cytokines, again in response to either TLR or CD40 stimulation. Finally, in coculture experiments, TLR10 differentiated dendritic cells exhibited a decreased capacity to activate T cells as measured by IL-2 and IFN-γ production. These data demonstrate that TLR10 is a novel regulator of innate immune responses and of the differentiation of primary human monocytes into effective dendritic cells.
Background: Children with bronchopulmonary dysplasia (BPD) who require invasive home mechanical ventilation (IHMV) are medically vulnerable and experience high caregiving and healthcare costs. Predictors for duration of IHMV in children with BPD remain unclear, which can make prognostication and decision-making challenging.Methods: A retrospective cohort study of children with BPD requiring IHMV was conducted from independent children's hospital records (2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020)(2021). The primary outcome was IHMV duration, defined as time from initial discharge home on IHMV until cessation of positive pressure ventilation (day and night). Two new variables were included: discharge age corrected for tracheostomy (DACT) (chronological age at discharge minus age at tracheostomy) and level of ventilator support at discharge (minute ventilation per kg per day). Univariable Cox regression was performed with variables of interest compared to IHMV duration. Significant nonlinear factors (p < 0.05) were included in the multivariable analysis.
Background Children with chronic lung disease (CLD) of prematurity who require invasive home mechanical ventilation (iHMV) are medically vulnerable and experience high caregiving and healthcare costs. Predictors for duration of iHMV remain unclear, which can make prognostication and decision-making challenging. Methods A retrospective cohort study of children with CLD of prematurity requiring invasive iHMV was conducted from an independent children’s hospital records (2005-2021). The primary outcome was iHMV duration, defined as time from initial discharge home on iHMV until cessation of positive pressure ventilation (day and night). Two new variables were included: corrected tracheostomy age (CTA) (chronological age at discharge minus age at tracheotomy) and level of ventilator support at discharge (minute ventilation per kg per day). Univariable Cox regression was performed with variables of interest compared to iHMV duration. Significant nonlinear factors (P<0.05) were included in the multivariable analysis. Results One-hundred-and-nineteen patients used iHMV primarily for CLD of prematurity. Patient median index hospitalization lasted 12 months (IQR 8.0,14.4). Once home, half of patients were weaned off iHMV by 36.0 months and 90% by 52.2 months. Being Hispanic/Lantix ethnicity (HR 0.14 (95% CI 0.04, 0.53), p<0.01) and having a higher CTA were associated with increased iHMV duration (HR 0.66 (CI 0.43, 0.98), p<0.05). Conclusions Disparity in iHMV duration exists among patients using iHMV after prematurity. Prospective multisite studies that further investigate new analytic variables, such as CTA and level of ventilator support, and address standardization of iHMV care are needed to create more equitable iHMV management strategies.
Toll-like receptors (TLRs) are important pattern recognition receptors involved in the activation of innate immune responses against foreign pathogens. Humans possess ten TLRs, of which TLR10 is the only remaining TLR without a known ligand, signaling pathway or cellular function. Recent data by our lab has shown for the first time a suppression of cellular innate immune responses in primary human monocytes that is mediated by a TLR10 monoclonal antibody. This study sought to expand on our initial observations by investigating the signaling pathways, gene expression and long-term consequences of TLR10 engagement on primary human monocytes. Our data shows that TLR10 engagement is sufficient to suppress both IL-6 and TNF-α induction in response to TLR4, TLR7/8 or CD40 stimulation. Cellular lysates show that the primary target of TLR10 signaling may be to inhibit phosphorylation of Akt and its downstream targets. To further this hypothesis, we have performed RNA sequencing on cellular extracts to determine which pathways are targeted by TLR10 signaling. Our data also suggests that these events also affect long-term differentiation of monocytes into macrophages and dendritic cells. Macrophages and dendritic cells differentiated in the presence of a TLR10 antibody exhibit suppressed differentiation markers such as CD80/CD86 and HLA-DR/CD16 respectively after four days of differentiation. These data show that TLR10 is a novel regulator of innate immune responses on primary human monocytes and may have eventual therapeutics benefits in chronic inflammatory and auto-immune diseases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.