NK-4 exerts selective regulatory effects on the activation and function of allergy-related Th2 cells

Kohno, Keizo; Koya‐Miyata, Satomi; Harashima, Akira; Ariyasu, Toshio; Ushio, Shimpei

doi:10.1371/journal.pone.0199666

Cited by 10 publications

(13 citation statements)

References 53 publications

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“…Furthermore, tissue-resident macrophages with phagocytic function can express CD206 [35]. We recently demonstrated that NK-4 suppresses the STAT6 signaling pathway in human dermal fibroblasts stimulated with IL-4 and TNF- [8]. Together, these results suggest that NK-4 increased CD206 expression in THP-1 macrophages independently of IL- Jurkat E6.1 (ATCC) cells were suspended at 1 x 10 6 cells/ml in complete medium and treated with 50 M H2O2 for 6 h at 37C to specifically induce apoptosis as described previously [13].…”

Section: Discussionmentioning

confidence: 99%

“…The global annual increase in the number of patients suffering from pressure and venous ulcers indicates a need for therapeutic approaches to restore impaired efferocytosis in chronic wounds [7]. NK-4 is a divalent cationic pentamethine trinuclear cyanine dye that contains three quinolinium rings, N-ethyl side chains, and two iodine anions [8]. We recently demonstrated that NK-4 abrogated the IL-4-driven cytokine production profile in human monocytic THP-1 cells from proinflammatory to anti-inflammatory [8].…”

Section: Introductionmentioning

confidence: 99%

“…NK-4 is a divalent cationic pentamethine trinuclear cyanine dye that contains three quinolinium rings, N-ethyl side chains, and two iodine anions [8]. We recently demonstrated that NK-4 abrogated the IL-4-driven cytokine production profile in human monocytic THP-1 cells from proinflammatory to anti-inflammatory [8]. In the current study, we investigated whether NK-4 polarizes PMA-differentiated THP-1 cells with a macrophage-like phenotype (THP-1 macrophages) toward an M1-like phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

Kohno

Koya‐Miyata

Harashima

et al. 2020

Preprint

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Background: NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results: NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-a production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-a to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-a production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion: It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves efferocytosis, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

Kohno

Koya‐Miyata

Harashima

et al. 2020

Preprint

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“…NK-4 is the common name of cryptocyanine O.A.1 (PubChem CID: 5489539). We recently demonstrated that NK-4 abrogated the IL-4-driven cytokine production pro le in human monocytic THP-1 cells from proin ammatory to antiin ammatory [8]. In the current study, we investigated whether NK-4 polarizes phorbol 12-myristate 13acetate (PMA)-differentiated THP-1 cells with a macrophage-like phenotype (THP-1 macrophages) toward an M1-like phenotype.…”

Section: Introductionmentioning

confidence: 96%

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

Kohno

Koya‐Miyata

Harashima

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase.Results: NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-a production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-a to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-a production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production.Conclusion: It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

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“…NK-4 (IUPAC name: 1-ethyl-4-[(1Z,3E,5E)-1-(1-ethylquinolin-1-ium-4-yl)-5-(1-ethylquinolin-4-ylidene)penta-1,3-dien-3-yl]quinolin-1-ium;iodide) is a divalent cationic pentamethine trinuclear cyanine dye that contains three quinolinium rings, N-ethyl side chains, and two iodine anions [ 8 ]. NK-4 is the common name of cryptocyanine O.A.1 (PubChem CID: 5489539).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

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NK-4 exerts selective regulatory effects on the activation and function of allergy-related Th2 cells

Cited by 10 publications

References 53 publications

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

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