Regulator of calcineurin 1 differentially regulates TLR-dependent MyD88 and TRIF signaling pathways

Abstract

Toll-like receptors (TLRs) recognize the conserved molecular patterns in microorganisms and trigger myeloid differentiation primary response 88 (MyD88) and/or TIR-domain-containing adapter-inducing interferon-β (TRIF) pathways that are critical for host defense against microbial infection. However, the molecular mechanisms that govern TLR signaling remain incompletely understood. Regulator of calcineurin-1 (RCAN1), a small evolutionarily conserved protein that inhibits calcineurin phosphatase activity, suppresses inflammation during Pseudomonas aeruginosa infection. Here, we define the roles for RCAN1 in P. aeruginosa lipopolysaccharide (LPS)-activated TLR4 signaling. We compared the effects of P. aeruginosa LPS challenge on bone marrow-derived macrophages from both wild-type and RCAN1-deficient mice and found that RCAN1 deficiency increased the MyD88-NF-κB-mediated cytokine production (IL-6, TNF and MIP-2), whereas TRIF-interferon-stimulated response elements (ISRE)-mediated cytokine production (IFNβ, RANTES and IP-10) was suppressed. RCAN1 deficiency caused increased IκBα phosphorylation and NF-κB activity in the MyD88-dependent pathway, but impaired ISRE activation and reduced IRF7 expression in the TRIF-dependent pathway. Complementary studies of a mouse model of P. aeruginosa LPS-induced acute pneumonia confirmed that RCAN1-deficient mice displayed greatly enhanced NF-κB activity and MyD88-NF-κB-mediated cytokine production, which correlated with enhanced pulmonary infiltration of neutrophils. By contrast, RCAN1 deficiency had little effect on the TRIF pathway in vivo. These findings demonstrate a novel regulatory role of RCAN1 in TLR signaling, which differentially regulates MyD88 and TRIF pathways.

Inflammation Drives Alternative First Exon usage to Regulate Immune Genes including a Novel Iron Regulated Isoform of Aim2

“…3A-C) (38,39) and Rcan1 (SFig. 3D-F) (40), as well as a previously uncharacterized inflammatory specific isoform of Ampd3 (SFig. 3G-I), in human and mouse primary macrophages using RT-PCR.…”

Baishouwu Extract Suppresses the Development of Hepatocellular Carcinoma via TLR4/MyD88/NF-κB Pathway

“…It had been suggested that DEN-induced liver injury was accompanied by elevation of plasma LPS level, and then LPS can transiently exaggerated DEN-induced liver damage (Yu et al, 2010). After binding to TLR4, two critical intracellular signaling pathways are triggered, including the myeloid differentiation primary response 88 (MyD88) dependent and MyD88-independent signaling cascades (Pang et al, 2018). The MyD88-dependent signal transduction activates NF-κB through activation of its inhibitory protein IκBα, which allows NF-κB nuclear translocation and controls the expression of a multitude of proinflammatory cytokines and other immune-related genes, such as TNF-α, IL-1, IL-1β, IL-6, and IL-12 (Shi et al, 2013; Li X. et al, 2015).…”

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

“…MyD88 activates the nuclear factor kappa light chain enhancer of activated B cells (NF-κB), allowing the activation of a multitude of pro-inflammatory cytokines and chemokines (IL-6, TNF-α, and the macrophage inflammatory protein (MIP)-2). TRIF drives the transcription of chemokines IFN-α and IFN-β, RANTES (regulated in the activation of normal expressed and secreted T cell expressed) and IP-10 (Interferon γ-inducible protein 10) [60]. A TLR4/MD2 agonistic monoclonal antibody, UT12, promoted host defence against chronic P. aeruginosa lung infection in mice, increasing neutrophil levels and concentrations of inflammatory MIP-2 in the lungs and improving bacterial clearance [61].…”