G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling

Steury, Michael D.; McCabe, Laura R.; Parameswaran, Narayanan

doi:10.1016/bs.ai.2017.05.003

Cited by 30 publications

(30 citation statements)

References 210 publications

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“…These observations likely account for attenuated experimental autoimmune encephalomyelitis severity in the CD6-deficient mouse and the beneficial use of anti-CD6 antibodies in multiple sclerosis treatment ( Consuegra-Fernández et al, 2018 ). T cell transendothelial migration (TEM) is guided by G protein–coupled receptors (GPCRs) specific for chemokines, and liganded GPCRs undergo phosphorylation by GRKs, the functional effect of which appears to be cell-type specific ( Steury et al, 2017 ). Among the novel proteins identified in the CD6 interactome, the presence of GRK6 and ARHGAP45 supports the involvement of CD6 in TEM.…”

Section: Discussionmentioning

confidence: 99%

The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation

Mori

Grégoire

Voisinne

et al. 2020

Journal of Experimental Medicine

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To determine the respective contribution of the LAT transmembrane adaptor and CD5 and CD6 transmembrane receptors to early TCR signal propagation, diversification, and termination, we describe a CRISPR/Cas9–based platform that uses primary mouse T cells and permits establishment of the composition of their LAT, CD5, and CD6 signalosomes in only 4 mo using quantitative mass spectrometry. We confirmed that positive and negative functions can be solely assigned to the LAT and CD5 signalosomes, respectively. In contrast, the TCR-inducible CD6 signalosome comprised both positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators of T cell activation. Moreover, CD6 associated independently of TCR engagement to proteins that support its implication in inflammatory pathologies necessitating T cell transendothelial migration. The multifaceted role of CD6 unveiled here accounts for past difficulties in classifying it as a coinhibitor or costimulator. Congruent with our identification of UBASH3A within the CD6 signalosome and the view that CD6 constitutes a promising target for autoimmune disease treatment, single-nucleotide polymorphisms associated with human autoimmune diseases have been found in the Cd6 and Ubash3a genes.

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Section: Discussionmentioning

confidence: 99%

The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation

Mori

Grégoire

Voisinne

et al. 2020

Journal of Experimental Medicine

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“…These included microbial metabolites such as the SCFAs butyrate, propionate, and acetate. SCFAs can act either as substrates for host cell metabolism and/or as signaling molecules, particularly induction of immune signaling cascades via G‐protein‐coupled receptors (GPCRs) 47 . Previous studies have implicated SCFA‐receptors signaling in chronic inflammatory diseases, which may occur via a variety of mechanisms.…”

Section: Discussionmentioning

confidence: 99%

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

et al. 2020

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The early life gut microbiota plays a crucial role in regulating and maintaining the intestinal barrier, with disturbances in these communities linked to dysregulated renewal and replenishment of intestinal epithelial cells. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period, and which host and microbial factors mediate these responses. Surprisingly, neonatal mice (Day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of liposaccharide (LPS), with Day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses. When we profiled microbiota and metabolites, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia, and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes, and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Antibiotic treatment of neonates restored LPS-induced small intestinal cell shedding, whereas adult fecal microbiota transplant alone had no effect.Our findings further support the importance of the early life window for microbiotaepithelial interactions in the presence of inflammatory stimuli and highlights areas for further investigation. K E Y W O R D S antibiotics, cell shedding, early life, fecal microbiota transplant, inflammation, intestinal epithelium, metabolites, microbiota 7076 | HUGHES Et al.

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“…These included microbial metabolites such as the SCFAs butyrate, propionate, and acetate. SCFAs can act either as substrates for host cell metabolism and/or as signalling molecules, particularly induction of immune signalling cascades via G-protein-coupled receptors (GPCRs) [37]. Previous studies have implicated SCFA-receptors signalling in chronic inflammatory diseases, which may correlate with the increased inflammatory responses observed in adult mice and enhanced pathological cell shedding [38].…”

Section: Discussionmentioning

confidence: 99%

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

Hughes

Schofield

Dalby

et al. 2019

Preprint

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AbstractThe gut microbiota plays a crucial role in regulating and maintaining the epithelial barrier, particularly during early life. Notably, patients with chronic intestinal inflammation have a dysregulated process of renewal and replenishment of the intestinal epithelial cell (IEC) barrier, which is linked to disturbances in the gut microbiota. To date, there are no studies focussed on understanding the impact of inflammatory cell shedding events during the early life developmental window, and which host and microbial factors mediate these responses. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period (day 14, 21, 29 and week 8). Surprisingly neonatal mice (day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of LPS, with day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses, although we did observe that neonatal mice had elevated anti-inflammatory (IL-10) responses. Notably, when we profiled microbiota and metabolites from these mice, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Faecal microbiota transplant (FMT) and antibiotic studies confirmed the importance of early life gut microbiota in cell shedding responses. In these studies, neonates treated with antibiotics restored LPS-induced small intestinal cell shedding, whereas adult FMT alone had no effect. Our findings further support the importance of the early life window for microbiota-epithelial interactions in the presence of inflammatory stimuli and highlight areas for further investigation to probe underlying mechanisms to drive therapeutic development within the context of chronic inflammatory intestinal diseases.

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G Protein-Coupled Receptor Kinases in the Inflammatory Response and Signaling

Cited by 30 publications

References 210 publications

The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation

The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

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