Immunostimulatory effects of RACK1 pseudosubstrate in human leukocytes obtained from young and old donors

Abstract

Aims of this study were to investigate the ability of RACK1 pseudosubstrate alone or in combination with classical immune stimuli to activate human leukocytes, and to restore age-associated immune defects.A total of 25 donors (17 old donors, 77–79 yrs; 8 young donors, 25–34 yrs) were enrolled. To evaluate the effect of RACK1 pseudosubstrate on cytokine production and CD86 expression the whole blood assay was used. Cultures were treated with RACK1 pseudosubstrate in the presence or absence of lipopolysaccharide (LPS) or phytohaemagglutinin (PHA) and incubated for 24 h or 48 h for LPS-induced CD86 expression, TNF-α, IL-6, IL-8, IL-10 production, and PHA-induced IL-4, IL-10, IFN-γ, respectively. RACK1 pseudosubstrate alone induced IL-6, IL-8, and CD86 expression in both young and old donors, and IFN-γ in old donors. In combination with LPS an increase in IL-8, IL-10 and TNF-α was observed, also resulting in restoration of age-associated defective production, while no changes in the other parameters investigated were found.Even if based on a small sample size, these results suggest the possibility to by-pass some of age-associated immune alterations, which may be beneficial in situations were natural immune stimulation is required, and highlight a different role of PKCβ in immune cells activation.

Underexpression of Receptor for Activated C Kinase 1 (RACK1) in Leukocytes from Patients with Severe Acute Pancreatitis

“…Moreover, a good positive correlation was observed between RACK-1 mRNA and protein levels and TNF-α or interleukin-8 release in THP-1 cells (Corsini et al 2014). Furthermore, a decreased expression level of RACK1 underlies immune deficits in aged people and Alzheimer's patients (Racchi et al 2006;Corsini et al 2015). RACK1 also plays an important role in the anti-inflammatory effects of glucocorticoids (Corsini et al 2014).…”

Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq

“…The co-functional modules included 97 E3 ligases, 65 E3 complex members and 3 ubiquitin-like domain proteins, 85 of which did not have prior literature evidence in DCs or inflammation, and can be deemed as novel functional annotations (Table S9), based on their co-membership and their target programs (Figure 2D). Three of the E3 ligase or complex members in the model are "authorities" in the E3 circuit, as their expression is impacted (positively and negatively) by a particularly high number of other E3s (Figure 3A and S4A,B): E3s Rack1 (which targets Hif1a and BimEL 49,52,69 ) and Rnf128 (Grail; regulates Tbk1 and interferon and antiviral response [70][71][72] ), and E3 complex member Socs3 (regulates Jak2 and gp130 and response to cytokines). All three have known roles in DC biology or inflammation: Rack1 suppresses type 1 IFN responses rendering mice more susceptible to viral infection 52 , Rnf128 targets the DC maturation marker Cd83 for degradation 72 , and Socs3 regulates JAK/STAT signaling, inflammation and macrophage polarization 73 .…”

RACK1 plays a critical role in mast cell secretion and Ca2+ mobilization by modulating F-actin dynamics

“…The ability of RACK1 to integrate various signaling pathways is important in immune cell response, since this process requires precise regulation of signaling between various receptors, changes in [Ca 2+ ] i , and cytoskeleton rearrangement (Ballek et al, 2016;Negoro et al, 2014;Ron et al, 2013;Yao et al, 2014). Modifications in the expression level of RACK1 have been associated with abnormal release of inflammatory mediators by immune cells (Corsini et al, 2021(Corsini et al, , 2015(Corsini et al, , 2014Yao et al, 2014). Additionally, the gene RACK1 (also known as GNB2L1), which encodes RACK1, appears to be involved in asthma (Hwang et al, 2008).…”