Abstract:
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.
journal_name
J Inflamm (Lond)journal_title
Journal of inflammation (London, England)authors
Kohno K,Koya-Miyata S,Harashima A,Tsukuda T,Katakami M,Ariyasu T,Ushio S,Iwaki Kdoi
10.1186/s12950-020-00267-zsubject
Has Abstractpub_date
2021-01-07 00:00:00pages
2issue
1issn
1476-9255pii
10.1186/s12950-020-00267-zjournal_volume
18pub_type
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