HIPK2 sustains inflammatory cytokine production by promoting endoplasmic reticulum stress in macrophages

Xu, Long; He, Fang; Xu, Dayuan; Wang, Guangyi

doi:10.3892/etm.2020.9301

Cited by 6 publications

(6 citation statements)

References 24 publications

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“…The previously reported that HIPK2 plays important role in inflammatory cytokine production [36]. In this work, the expression of HIPK2 was a prominent upregulation in RA tissues and cells.…”

Section: Discussionsupporting

confidence: 53%

Circ_0025908 regulates cell vitality and proliferation via miR-137/HIPK2 axis of rheumatic arthritis

et al. 2021

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Background Rheumatic arthritis (RA) is an autoimmune disease with bad effects. Recent researches have shown that circular RNAs (circRNAs) could affect the progress of RA, but the mechanism still indistinct. In this work, we explored the roles of circ_0025908 in RA. Methods The levels of circ_0025908, microRNA-137 (miR-137), and mRNA of homeodomain-interacting protein kinase 2 (HIPK2) were detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) in RA tissues. Meanwhile, the level of HIPK2 was quantified by Western blot analysis. Besides, the cell functions were examined by CCK8 assay, EdU assay, flow cytometry assay, ELISA, and Western blot. Furthermore, the interplay between miR-137 and circ_0025908 or HIPK2 was detected by dual-luciferase reporter assay. Results The levels of circ_0025908 and HIPK2 were upregulated, and the miR-137 level was decreased in RA tissues in contrast to that in normal tissues. For functional analysis, circ_0025908 deficiency inhibited cell vitality, cell mitotic cycle, cell proliferation, and immunoreaction in RA cells, whereas promoted cell apoptosis. Moreover, miR-137 was confirmed to repress the progression of RA cells by suppressing HIPK2. In mechanism, circ_0025908 acted as a miR-137 sponge to regulate the level of HIPK2. Conclusion Circ_0025908 facilitates the development of RA through increasing HIPK2 expression by regulating miR-137, which also offered an underlying targeted therapy for RA treatment.

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Section: Discussionsupporting

confidence: 53%

Circ_0025908 regulates cell vitality and proliferation via miR-137/HIPK2 axis of rheumatic arthritis

et al. 2021

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“…A recent study suggests that HIPK2 sustains inflammatory cytokine production by promoting endoplasmic reticulum stress in macrophages, which shows the decreased phosphorylation levels of p65 in LPS-stimulated Hipk2 knockdown PEMs (43). However, we did not observe significant changes of p65 phosphorylation after Hipk2 knockdown (SI Appendix, Fig.…”

Section: Discussionmentioning

confidence: 54%

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis

Zhang

Feng

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-κB–mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-κB activation will provide important therapeutic application. Here, we have identified that homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPS-induced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk2+/− bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2−/− BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2-HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.

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“…HIPK2 regulates PPM1D protein levels by inducing its degradation in DNA-damaged cells, triggering activation of the DNA repair pathway 133 . HIPK2 expression increases in LPS-stimulated macrophages, and its knockdown attenuates the expression of inflammatory cytokines 134, 135 . S46 is also a HIPK2 substrate.…”

Section: Discussionmentioning

confidence: 99%

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Trifiletti¹,

Manusama

et al. 2021

Preprint

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Pediatric acute onset neuropsychiatric syndrome (PANS) is viewed as an autoimmune/autoinflammatory condition characterized by the abrupt onset of severe neurological and psychiatric symptoms, in particular obsessive-compulsive disorder (OCD), tics, anxiety, mood swings, irritability, and restricted eating, often triggered by infections. However, direct evidence of autoimmunity, infections, or a proinflammatory state is often lacking, and there is no unifying pathogenic pathway. This could be due to underlying genetic heterogeneity, which could lead to the development of PANS through different cellular and molecular pathways. Unfortunately, little is known about the genetic basis of PANS. Consequently, we carried out whole exome sequencing (WES) on a U.S. cohort of 386 cases who met diagnostic criteria for PANS, including 133 family triads, and whole genome sequencing (WGS) on ten cases from the European Union, who were selected for WGS because of severe PANS symptoms. We focused on identifying potentially deleterious genetic variants that were either de novo or ultra-rare with a minor allele frequency (MAF) < 0.001. Candidate mutations were found in 11 genes: PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1 in a total of 20 cases, which included two sets of siblings, and two or more unrelated subjects with ultra-rare variants in SGCE, NLRC4, RAG1, and SHANK3. The PANS candidate genes we identified separate into two broad functional categories. One group regulates peripheral innate and adaptive immune responses (e.g., PPM1D, CHK2, NLRC4, RAG1, PLCG2), some of which also influence microglia function. Another is expressed primarily at neuronal synapses or directly modulates synaptic function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). These neuronal PANS candidate genes are often mutated in autism spectrum disorder, developmental disorders, and myoclonus-dystonia. In fact, eight out of 20 cases in this study developed PANS superimposed on a preexisting neurodevelopmental disorder. There is, however, clinical overlap between these two groups and some crossover expression (e.g., some neuronal genes are expressed in immune cells and vice versa) that diminishes the neuronal/immune dichotomy. Genes in both categories are also highly expressed in the enteric nervous system, and in the choroid plexus and brain vasculature, suggesting they might contribute to a breach in the blood-CSF barrier and blood-brain barrier (BBB) that would permit the entry of autoantibodies, inflammatory cytokines, chemokines, prostaglandins, and autoantibodies into the brain. Thus, PANS is a genetically heterogeneous condition that can occur as a stand-alone neuropsychiatric condition or co-morbid with neurodevelopmental disorders, with candidate genes functioning at several levels of the neuroinflammatory axis.

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HIPK2 sustains inflammatory cytokine production by promoting endoplasmic reticulum stress in macrophages

Cited by 6 publications

References 24 publications

Circ_0025908 regulates cell vitality and proliferation via miR-137/HIPK2 axis of rheumatic arthritis

Circ_0025908 regulates cell vitality and proliferation via miR-137/HIPK2 axis of rheumatic arthritis

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

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