Regulation of lipopolysaccharide‐induced inflammatory response and endotoxemia by β‐arrestins

Abstract

β-arrestins are scaffolding proteins implicated as negative regulators of TLR4 signaling in macrophages and fibroblasts. Unexpectedly, we found that β-arrestin-1 (β-arr-1) and −2 knockout (KO) mice are protected from TLR4-mediated endotoxic shock and lethality. To identify the potential mechanisms involved, we examined the plasma levels of inflammatory cytokines/chemokines in the wild type (WT) and β-arr-1 and −2 KO mice after lipopolysaccharide (LPS, a TLR4 ligand) injection. Consistent with lethality, LPS-induced inflammatory cytokine levels in the plasma were markedly decreased in both β-arr-1 and −2 KO, compared to WT mice. To further explore the cellular mechanisms, we obtained splenocytes (separated into CD11b+ and CD11b−populations) from WT, β-arr-1 and −2 KO mice and examined the effect of LPS on cytokine production. Similar to the in vivo observations, LPS-induced inflammatory cytokines were significantly blocked in both splenocyte populations from the β-arr-2 KO compared to the WT mice. This effect in the β-arr-1 KO mice, however, was restricted to the CD11b− splenocytes. Our studies further indicate that regulation of cytokine production by β-arrestins is likely independent of MAPK and IκBα-NFκB pathways. Our results, however, suggest that LPS-induced chromatin modification is dependent on β-arrestin levels and may be the underlying mechanistic basis for regulation of cytokine levels by β-arrestins in vivo. Taken together, these results indicate that β-arr-1 and −2 mediate LPS-induced cytokine secretion in a cell-type specific manner and that both β-arrestins have overlapping but non-redundant roles in regulating inflammatory cytokine production and endotoxic shock in mice.

β-arrestin1 Is Critical for the Full Activation of NLRP3 and NLRC4 Inflammasomes

“…Afterward, other findings indicated that the functions of b-arrestins are pleiotropic (35,36). Nevertheless, we found that b-arrestin1 had no effect on IL-6 and pro-IL-1b production, but it regulated IL-1b secretion by regulating inflammasome activation.…”

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

“…NMDA activation-induced dendrite spine remodeling in neurons is dependent on the scaffolding protein ␤-arrestin-2 (24). This was of interest because ␤-arrestin-2 is known to modulate LPS-induced inflammatory responses, but its role in inflammasome activation is not known (5,22,25,33). Our results clearly show that aspartate-dependent downregulation of inflammasome function in vitro and in vivo is dependent on ␤-arrestin-2.…”

Lipopolysaccharide-induced inflammation in monocytes/macrophages is blocked by liposomal delivery of G_i-protein inhibitor

“…22 Using a well-established cellular model of inflammation, the aim of the present work was to evaluate the potential of a G i inhibitor encapsulated in Lipo in reducing the inflammatory effects induced by LPS in monocytes/macrophages, such as the activation of MAPK-signaling pathways, inflammatory cytokine secretion, monocyte adhesion, and chemotaxis. 23 G proteins are heterotrimers comprising α-, β-, and γ-subunits that dissociate in response to proinflammatory stimuli after activation of G-protein-coupled receptors. The free G α and G βγ subunits can then activate different mediators Figure 5 effect of lipo/gOT on monocyte adhesion to endothelium.…”