Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis

Kaya, Berna; Doñas, Cristian; Wuggenig, Philipp; Diaz, Oscar E.; Morales, Rodrigo A.; Melhem, Hassan; Hernández, Pedro P.; Kaymak, Tanay; Das, Srustidhar; Hrúz, Petr; Franc, Yannick; Geier, Florian; Ayata, C. Korcan; Villablanca, Eduardo J.; Niess, Jan Hendrik

doi:10.1016/j.celrep.2020.107979

Cited by 69 publications

(85 citation statements)

References 60 publications

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“…To characterize the impact of Gpr35 on the epithelial barrier, we made use of the zebrafish ( Dario rerio ) model. Previously, we CRISPR-targeted two GPR35 paralogs in zebrafish, gpr35a and gpr35b , which revealed that the latter is more similar in function to human GPR35 (Kaya et al, 2020). Goblet cell numbers in gpr35b deficient ( gpr35b uu19b2 ) zebrafish were decreased compared to Gpr35 wt larvae (Figures 1A and 1B).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, susceptibility to C. rodentium increased at an early time point when the innate and not the adaptive immune system is in the process of clearing the infection, further indicating that impaired goblet cells contribute to the increased C. rodentium susceptibility in epithelial Gpr35 -deficient mice. We have previously demonstrated that GPR35 + macrophages show higher transcript levels of pro-inflammatory cytokines, including Il1b and Tnf (Kaya et al, 2020). In turn, these cytokines have been shown to potentiate intestinal permeability (Neurath, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Gpr35 -tdTomato, Gpr35 −/− and Gpr35 f/f animals were constructed as previously described (Kaya et al, 2020). Gpr35 -tdTomato mice were crossed with Cx3cr1 -GFP mice to generate the double reporter mouse line.…”

Section: Methodsmentioning

confidence: 99%

“…Genome-wide association studies on GPR35 single nucleotide polymorphisms indicated that the rs3749171 variant of GPR35, responsible for T108M substitution, might be related to the pathogenesis of UC (Ellinghaus et al, 2013; Imielinski et al, 2009). GPR35 remains an orphan GPCR, although we recently demonstrated that lysophosphatidic acid (LPA) is a potential endogenous ligand for GPR35 using cell-based assays (Kaya et al, 2020). Besides LPA, several other candidates, including the tryptophan metabolite kynurenic acid (Wang et al, 2006) and the chemokine CXCL17 (Maravillas-Montero et al, 2015) can act as potential endogenous ligands for GPR35.…”

Section: Introductionmentioning

confidence: 99%

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Epithelial GPR35 protects fromCitrobacter rodentiuminfection by preserving goblet cells and mucosal barrier integrity

Melhem

Kaya

Kaymak

et al. 2021

Preprint

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Goblet cells are essential for maintaining intestinal health and for the defense against invasive bacterial infection. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. Here we found that epithelial Gpr35 plays a critical role in goblet cell function. Genetic deletion of Gpr35 in epithelial cells but not in from macrophages results in goblet cell depletion and dysbiosis, rendering these mice more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows how the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Epithelial GPR35 protects fromCitrobacter rodentiuminfection by preserving goblet cells and mucosal barrier integrity

Melhem

Kaya

Kaymak

et al. 2021

Preprint

Self Cite

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“…2D, E). CX3CR1 is a maker of residential macrophages in the mucosa 25 . Lack of QKI expression exerted no effect on the typical resident intestinal macrophage (CD45 + CD11b + F4/80 + CX3CR1 + ) population (Fig.…”

Section: Qki Deletion Elevated the Proportion Of M1 Macrophages In Thmentioning

confidence: 99%

Loss of QKI in macrophage aggravates inflammatory bowel disease through amplified ROS signaling and microbiota disproportion

et al. 2021

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Inflammatory bowel disease (IBD) is a refractory chronic inflammatory illness of the gastrointestinal (GI) tract. Macrophage exerts an important role in IBD development. QKI, as an RNA binding protein, was related with inflammatory responses in bacterial infections by regulating the polarization of macrophages. Therefore, we suspected that QKI-regulated macrophages have the potential to play a certain role in IBD and the underlying mechanism. Our results demonstrated that the mice with macrophage-specific deletion of QKI induced with dextran sodium sulfate (DSS) are more susceptible to IBD development, exhibited a severe leaky gut barrier phenotype and higher intense oxidative stress, which are rescued by treating with butylated hydroxyanisole (BHA), an agonist of NRF2. Mechanically, we observed that Keap1 mRNA in the nucleus was exported to the cytoplasm after LPS stimuli in parallel with QKI reductions, and the removal of QKI by shRNA facilitated Keap1 mRNA nuclear exporting and expression in cytoplasm, consequently NRF2 activation in nucleus was weakened, and led to the impaired antioxidant abilities. In addition, mice models of fecal microbiota transplant (FMT) and the co-culturing of mice epithelia cells with feces derived from the DSS-treated QKI-deficit mice revealed consistently aggravated colitis along with a severe oxidative stress; 16S sequencing analysis substantiated the altered compositions of commensal bacteria too. Overall, the current study represents the first effort to explore the anti-oxidant role of QKI in the intestinal macrophage via post-transcriptional regulation of Keap1 mRNA localization and the relevant NRF2 antioxidant signaling, and the disproportional changes in the microbiota were attributable to the mediation of pathogenic damage in the IBD development of QKI-deficit mice.

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Application of zebrafish in the study of the gut microbiome

Zhong

et al. 2022

Anim Models and Exp Med

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The gut microbiome is widely acknowledged to coexist with the animal host, consisting of symbiotic and pathogenic bacteria in a dynamic balance state that produce a wide variety of signaling molecules. These bacteria colonize the intestine and perform functions the host itself cannot accomplish; in turn, they rely on the habitat provided by the host. A healthy gut microbiome plays a significant and irreplaceable role in determining the host's overall health.Zebrafish is an omnivorous freshwater fish that belongs to the small carp family. It has been widely used for research purposes on embryology and tissue regeneration, molecular genetics, reproductive biology, and toxicology given its numerous advantages, including high fecundity, short lifespan, highly annotated genome, optical

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Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis

Cited by 69 publications

References 60 publications

Epithelial GPR35 protects fromCitrobacter rodentiuminfection by preserving goblet cells and mucosal barrier integrity

Epithelial GPR35 protects fromCitrobacter rodentiuminfection by preserving goblet cells and mucosal barrier integrity

Loss of QKI in macrophage aggravates inflammatory bowel disease through amplified ROS signaling and microbiota disproportion

Application of zebrafish in the study of the gut microbiome

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