https://escholarship.org/content/qt4431p9mq/qt4431p9mq.pdf?t=qeh5tn

The Global Phosphorylation Landscape of SARS-CoV-2 Infection.

TNF and MAP kinase signalling pathways

Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action.

Objectives Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. The hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. Results First, we demonstrated that TNF ΔARE mice show typical inflammatory features highly reminiscent of SpA. The first signs of inflammation were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF ΔARE mice significantly suppressed inflammation of the Achilles tendon compared with weight bearing controls. Erk1/2 signalling plays a crucial role in mechanotransduction-associated inflammation. Furthermore, new bone formation is strongly promoted at entheseal sites by biomechanical stress and correlates with the degree of inflammation. Conclusions These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.

https://ard.bmj.com/content/annrheumdis/73/2/437.full.pdf

Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells

Apoptosis of inflammatory cells and their subsequent clearance (efferocytosis) by macrophages (Mφs) are key mechanisms orchestrating successful resolution of inflammation. Although the powerful proinflammatory agents lipopolysaccharide (LPS) and tumor necrosis factor α (TNF-α) influence rates of inflammatory cell apoptosis, little is known about their effects on efferocytosis. We have demonstrated that LPS and TNF-α potently inhibit efferocytosis of neutrophils by monocyte-derived Mφs. Inhibition was both concentration and time dependent, although the effect of TNF-α was more rapid. We have found that soluble TNF receptor-I attenuated LPS inhibition of phagocytosis, indicating that TNF-α production is critical. Inhibition of efferocytosis by LPS was found to be positively associated with Mφ production of TNF-α, but negatively with interleukin-10 (IL-10) release. A critical role for IL-10 in the regulation of phagocytosis was suggested by 2 important findings: LPS inhibition was observed more rapidly in th...

/pdf/macrophage-phagocytosis-of-apoptotic-neutrophils-is-u642zacjsi.pdf

Macrophage phagocytosis of apoptotic neutrophils is critically regulated by the opposing actions of pro-inflammatory and anti-inflammatory agents: key role for TNF-α

Tumor necrosis factor alpha (TNF-α) is a critical mediator of inflammation, and its production is tightly regulated, with control points operating at nearly every step of its biosynthesis. We sought to identify uncharacterized TNF-α 3' untranslated region (3'UTR)-interacting proteins utilizing a novel screen, termed the RNA capture assay. We identified CARHSP1, a cold-shock domain-containing protein. Knockdown of CARHSP1 inhibits TNF-α protein production in lipopolysaccharide (LPS)-stimulated cells and reduces the level of TNF-α mRNA in both resting and LPS-stimulated cells. mRNA stability assays demonstrate that CARHSP1 knockdown decreases TNF-α mRNA stability from a half-life (t(1/2)) of 49 min to a t(1/2) of 22 min in LPS-stimulated cells and from a t(1/2) of 29 min to a t(1/2) of 24 min in resting cells. Transfecting CARHSP1 into RAW264.7 cells results in an increase in TNF-α 3'UTR luciferase expression in resting cells and CARHSP1 knockdown LPS-stimulated cells. We examined the functional effect of inhibiting Akt, calcineurin, and protein phosphatase 2A and established that inhibition of Akt or calcineurin but not PP2A inhibits CARHSP1 function. Subcellular analysis establishes CARHSP1 as a cytoplasmic protein localizing to processing bodies and exosomes but not on translating mRNAs. We conclude CARHSP1 is a TNF-α mRNA stability enhancer required for effective TNF-α production, demonstrating the importance of both stabilization and destabilization pathways in regulating the TNF-α mRNA half-life.

CARHSP1 Is Required for Effective Tumor Necrosis Factor Alpha mRNA Stabilization and Localizes to Processing Bodies and Exosomes

Extracellular Signal-regulated Kinase Regulation of Tumor Necrosis Factor-α mRNA Nucleocytoplasmic Transport Requires TAP-NxT1 Binding and the AU-rich Element

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CARHSP1 Is Required for Effective Tumor Necrosis Factor Alpha mRNA Stabilization and Localizes to Processing Bodies and Exosomes

Extracellular Signal-regulated Kinase Regulation of Tumor Necrosis Factor-α mRNA Nucleocytoplasmic Transport Requires TAP-NxT1 Binding and the AU-rich Element