LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria

Long noncoding RNA (lncRNA) plays a critical role in many biological processes, such as cell differentiation and development. However, few studies about lncRNAs regulating the differentiation and development of myeloid-derived suppressor cells (MDSCs) exist. In this study, we identified a lncRNA pseudogene, Olfr29-ps1, which was expressed in MDSCs and upregulated by the proinflammatory cytokine IL6. The Olfr29-ps1 in vertebrates is conserved, and the similarity between the Olfr29-ps1 and human OR1F2P sequence is 43%. This lncRNA promoted the immunosuppressive function and differentiation of monocytic (Mo-)MDSCs in vitro and in vivo. It directly sponged miR-214-3p to downregulate miR-214-3p, which may target MyD88 to modulate the differentiation and development of MDSCs. The functions of Olfr29-ps1 were dependent on IL6-mediated N 6-methyladenosine (m6A) modification, which not only enhanced Olfr29-ps1, but also promoted the interaction of Olfr29-ps1 with miR-214-3p. Thus, our results demonstrated that the pseudogene Olfr29-ps1 may regulate the differentiation and function of MDSCs through a m6A-modified Olfr29-ps1/miR-214-3p/MyD88 regulatory network, revealing a mechanism for the regulation of myeloid cells and also providing potential targets for antitumor immunotherapy.

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“…Western blot was performed as described previously (25). Briefly, cells were harvested at the indicated times and rinsed twice with ice-cold PBS.…”

Section: Western Blotmentioning

confidence: 99%

The Pseudogene Olfr29-ps1 Promotes the Suppressive Function and Differentiation of Monocytic MDSCs

Shang

Gao

Tang

et al. 2019

Cancer Immunology Research

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“…Cells were collected and rinsed twice with ice-cold PBS, incubated with FITC-, PE-, percy5.5-, or APC-labeled antibodies for 30 minutes in PBS with 1% FBS according to our previous method (19). After washed twice, cells were resuspended in PBS and analyzed using a FACScan flow cytometer (BD Biosciences).…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Cell extracts were prepared with lysis buffer and centrifuged at 13,000 Â g for 10 minutes at 4 C. Protein samples were electrophored using 12% polyacrylamide gels and transferred to PVDF membranes. After the membranes were blocked with 5% skim milk powder for 1 hour at room temperature, they were incubated with first antibody in TBST overnight at 4 C. Secondary antibodies with horseradish peroxidase (HRP; 1:5,000) were labeled according to our method previously reported (19). The signals were checked by autoradiography film when HRP substrate was added to the membranes.…”

Section: Western Blotmentioning

confidence: 99%

Lnc-C/EBPβ Negatively Regulates the Suppressive Function of Myeloid-Derived Suppressor Cells

Gao

Sun

Shang

et al. 2018

Cancer Immunology Research

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Myeloid-derived suppressor cells (MDSC) are regulators of immune responses in cancer. The differentiation and function of these MDSCs may be regulated through multiple factors, such as microRNAs. However, the effect of long noncoding RNAs (lncRNA) on the differentiation and function of MDSCs is poorly understood. We identified a long noncoding RNA (lncRNA) named in MDSCs, which may control suppressive functions of MDSCs. could be induced in and tumor and inflammatory environments. It regulated a set of target transcripts, such as Arg-1, NOS2, NOX2, and COX2, to control immune-suppressive function and differentiation of MDSCs. This lncRNA was also able to bind to the C/EBPβ isoform LIP to inhibit the activation of C/EBPβ. We also found that the conserved homologue has a similar function to murine These findings suggest a negative feedback role for in controlling the immunosuppressive functions of MDSC in the tumor environment..

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“…LRRC19 is a recently identified member that has four LRR motifs at its extracellular domain and is strongly expressed in kidney, spleen and intestine in mouse. 11,12 Expression of LRRC19 can induce multiple TLR ligand-mediated NFkB activation in 293T cells. In vivo animal model with LRRC19 knockout showed the impaired production of cytokine, chemokine and anti-microbial substances in kidney and gut tissues through downregulation of TRAF2/6-mediated NFkB and MAPK signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

“…In vivo animal model with LRRC19 knockout showed the impaired production of cytokine, chemokine and anti-microbial substances in kidney and gut tissues through downregulation of TRAF2/6-mediated NFkB and MAPK signaling pathways. 11,13 Recently a microarray based transcriptome study in rat pressure ulcer model has revealed the upregulation of LRRC19 gene associated with the lesion progress. 14 Therefore, it would be intriguing to validate the change of LRRC19 and investigate its functional implication in pressure ulcer pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Suppression of LRRC19 promotes cutaneous wound healing in pressure ulcers in mice

Sun

Wang

2018

Organogenesis

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The ischemia-reperfusion (I/R) induced skin lesion has been identified as primary cause of pressure ulcer. Better understanding of the mechanism is required for new therapy development. Leucine rich repeat containing protein 19 (LRRC19) is a recently discovered transmembrane protein containing leucine-rich repeats and plays a role in immune response. To investigate the role of LRRC19 in pressure ulcers, mouse ulcer model was established with two cycles of I/R. The expression of LRRC19 was assessed during injury. siRNA mediated LRRC19 downregulation was applied to investigate the disease severity, immune cell infiltration and pro-inflammatory cytokines production. The primary skin fibroblasts were stimulated with IL-1β to dissect the molecular mechanism. LRRC19 was readily induced in I/R induced lesion site in a pattern mimicking the disease progress as measured by wound area. Knockdown of LRRC19 by siRNA significantly alleviated the disease severity and attenuated immune cell infiltration and pro-inflammatory cytokines production. In primary skin fibroblast model, siRNA knockdown of LRRC19 suppressed IL-1β mediated NFκB activation and its downstream cytokines production. LRRC19 was a novel factor for I/R-induced tissue damage by promoting NFκB dependent pro-inflammatory response. Our results supported that LRRC19 could be a potential therapeutic target for pressure ulcers.

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LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria

Cited by 27 publications

References 44 publications

The Pseudogene Olfr29-ps1 Promotes the Suppressive Function and Differentiation of Monocytic MDSCs

The Pseudogene Olfr29-ps1 Promotes the Suppressive Function and Differentiation of Monocytic MDSCs

Lnc-C/EBPβ Negatively Regulates the Suppressive Function of Myeloid-Derived Suppressor Cells

Suppression of LRRC19 promotes cutaneous wound healing in pressure ulcers in mice

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