Selective Pharmaceutical Inhibition of PARP14 Mitigates Allergen-Induced IgE and Mucus Overproduction in a Mouse Model of Pulmonary Allergic Response

Eddie, Alex M.; Chen, Kevin W; Schenkel, Laurie B.; Swinger, Kerren K.; Molina, Jennifer R.; Kunii, Kaiko; Raybuck, Ariel; Keilhack, Heike; Gibson‐Corley, Katherine N.; Niepel, Mario; Peebles, R. Stokes; Boothby, Mark; Cho, Sung Hoon

doi:10.4049/immunohorizons.2100107

Cited by 7 publications

(5 citation statements)

References 94 publications

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“…These motifs are present in the promoter region of interleukin-4 (Il-4) and Il-5 and PARP14 seems to have a role in the expression of T helper type 2 (Th2) cytokines [ 120 ]. This is further supported by findings of a role of PARP14 in allergic reactions in mice [ 121 ].…”

Section: The Ifn-regulated Subclass Of Parpssupporting

confidence: 72%

IFN-Induced PARPs—Sensors of Foreign Nucleic Acids?

2023

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Cells have developed different strategies to cope with viral infections. Key to initiating a defense response against viruses is the ability to distinguish foreign molecules from their own. One central mechanism is the perception of foreign nucleic acids by host proteins which, in turn, initiate an efficient immune response. Nucleic acid sensing pattern recognition receptors have evolved, each targeting specific features to discriminate viral from host RNA. These are complemented by several RNA-binding proteins that assist in sensing of foreign RNAs. There is increasing evidence that the interferon-inducible ADP-ribosyltransferases (ARTs; PARP9—PARP15) contribute to immune defense and attenuation of viruses. However, their activation, subsequent targets, and precise mechanisms of interference with viruses and their propagation are still largely unknown. Best known for its antiviral activities and its role as RNA sensor is PARP13. In addition, PARP9 has been recently described as sensor for viral RNA. Here we will discuss recent findings suggesting that some PARPs function in antiviral innate immunity. We expand on these findings and integrate this information into a concept that outlines how the different PARPs might function as sensors of foreign RNA. We speculate about possible consequences of RNA binding with regard to the catalytic activities of PARPs, substrate specificity and signaling, which together result in antiviral activities.

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Section: The Ifn-regulated Subclass Of Parpssupporting

confidence: 72%

IFN-Induced PARPs—Sensors of Foreign Nucleic Acids?

2023

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“…First of all, these studies are fuelled by the genetic findings where body-wide deficiency of Parp14 in mice diminished the intensity of allergic reactions 11,12,34 . To this end, one ART activity inhibitor was recently shown to reduce pulmonary allergic response in mice 35 and one ART activity inhibitor entered clinical trials in atopic dermatitis (Phase I, NCT05215808). Secondly, in vitro genetic findings have demonstrated that Parp14 inactivation in macrophages skews them toward a pro-inflammatory IFN-γ-driven M1 phenotype while reducing the IL-4-driven M2 phenotype 13 .…”

Section: Discussionmentioning

confidence: 99%

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Vedantham,

Polari,

Poosakkannu

et al. 2024

Preprint

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Inflammatory bowel disease (IBD) is a debilitating and relapsing chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly (ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, using a biobank IBD patient cohort as well as two mouse models of colitis, i.e., the IBD-mimicking oral dextran sulfate sodium (DSS) exposure model, and the oral Salmonella exposure model. Parp14 was expressed in the human colon, by cells in the lamina propria, but, in particular, by the epithelial cells with a typical granular staining pattern in the cytosol. The same Parp14 staining pattern was evidenced in both colitis models. Body-wide genetic deficiency of Parp14 in C57BL/6N background sensitized mice to DSS colitis. The Parp14-deficient mice displayed increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss and immune cell infiltration. The absence of Parp14 did not affect the mouse colon bacterial microbiota based on PacBio long read sequencing. Also, the colon leukocyte populations of Parp14-deficient mice were normal based on flow cytometry. In contrast, we witnessed an altered transcriptional signature in Parp14-deficient mice with bulk tissue RNA-Seq. Gene Ontology (GO)-based classification of differentially expressed genes demonstrated that the colon transcriptional signature of Parp14-deficient mice was dominated by abnormalities in inflammation and infection responses both prior and after the 1-week DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

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“…First of all, these studies are fueled by the genetic findings that a body‐wide deficiency of Parp14 in mice diminished the intensity of allergic reactions 11,12,47 . To this end, one ART activity inhibitor was recently shown to reduce pulmonary allergic response in mice 48 and one ART activity inhibitor entered clinical trials for atopic dermatitis (Phase I, NCT05215808). Secondly, in vitro genetic findings have demonstrated that Parp14 inactivation in macrophages skews them toward a pro‐inflammatory IFN‐γ‐driven M1 phenotype while reducing the IL‐4‐driven M2 phenotype 13 .…”

Section: Discussionmentioning

confidence: 99%

Body‐wide genetic deficiency of poly(ADP‐ribose) polymerase 14 sensitizes mice to colitis

Vedantham,

Polari,

Poosakkannu

et al. 2024

The FASEB Journal

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Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly(ADP‐ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with an IBD patient cohort as well as two mouse colitis models, that is, IBD‐mimicking oral dextran sulfate sodium (DSS) exposure and oral Salmonella infection. Parp14 was expressed in the human colon by cells in the lamina propria, but, in particular, by the epithelial cells with a granular staining pattern in the cytosol. The same expression pattern was evidenced in both mouse models. Parp14‐deficiency caused increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss, and immune cell infiltration in DSS‐exposed mice. The absence of Parp14 did not affect the mouse colon bacterial microbiota. Also, the colon leukocyte populations of Parp14‐deficient mice were normal. In contrast, bulk tissue RNA‐Seq demonstrated that the colon transcriptomes of Parp14‐deficient mice were dominated by abnormalities in inflammation and infection responses both prior and after the DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

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Selective Pharmaceutical Inhibition of PARP14 Mitigates Allergen-Induced IgE and Mucus Overproduction in a Mouse Model of Pulmonary Allergic Response

Cited by 7 publications

References 94 publications

IFN-Induced PARPs—Sensors of Foreign Nucleic Acids?

IFN-Induced PARPs—Sensors of Foreign Nucleic Acids?

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Body‐wide genetic deficiency of poly(ADP‐ribose) polymerase 14 sensitizes mice to colitis

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