SUMOylation of KLF4 promotes IL-4 induced macrophage M2 polarization

Wang, Kezhou; Wei, Zhou; Cai, Qi; Cheng, Jinke; Cai, Rong; Rong, Xing

doi:10.1080/15384101.2016.1269045

Cited by 35 publications

(29 citation statements)

References 46 publications

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“…On the other hand, MCPIP1 may also modify Klf4 ubiquitination, and thereby alter its regulatory effects on cellular processes such as cell growth, proliferation, and differentiation [48,49]. Indeed, Klf4 sumoylation promotes IL-4-induced macrophage M2 polarization [50]. Finally, the long-term effects of Klf4 against lipopolysaccharide-induced inflammation remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

Jia

Han

et al. 2018

Cell Physiol Biochem

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Background/Aims: Inflammation is an essential component of innate immunity against pathogens, but is tightly regulated, such as by Krüppel-like factor 4 (Klf4), to prevent injury. Klf4 also regulates macrophage polarization, although the mechanisms underlying both functions are poorly understood. The aim of this study was to investigate whether and how Klf4 prevents unregulated inflammation. Methods: The bone marrow-derived macrophages and RAW264.7 cell line were used. Quantitative real-time PCR was used to determine inflammatory cytokines (IL-1β, TNF-α, IL-6 and MCP-1), Klf4 and MCPIP1 transcript levels. Extraction of nuclear and cytoplasmic proteins and Immunoblotting were used to determine Klf4, MCPIP1, relative kinases from NF-κB pathway and K63-linked polyubiquitins expression in nucleus and cytoplasm separately. Dual luciferase reporter assay was used to analyze whether Klf4 mediate MCPIP1 transcription. Immunoprecipitation was used to determine the protein interaction among Klf4, MCPIP1, TRAF6 and K63-linked polyubiquitins. Secretion of IL-1β and TNF-α into sera in mice was measured by Enzyme-linked immunosorbent assay. Results: We found that exposure to lipopolysaccharides suppresses Klf4 expression, even as it induces release of pro-inflammatory cytokines. Strikingly, Klf4 overexpression significantly lowered cytokine secretion and NF-κB signaling in the cytoplasm following exposure to lipopolysaccharide, even though Klf4 was exclusively nuclear. The cytoplasmic effects are likely mediated by MCP-1 induced protein 1 (MCPIP1), a deubiquitinase and a key modulator of inflammation that accumulates both in the nucleus and cytoplasm in response to Klf4. Indeed, binding between MCPIP1 and K63 polyubiquitins is attenuated in macrophages overexpressing Klf4, suggesting that MCPIP1 is an intermediator induced by Klf4 in the nucleus to remove K63 polyubiquitins from TRAF6 in the cytoplasm, and thereby impede NF-κB and inflammatory signaling. Importantly, Klf4 overexpression in mice alleviated sepsis symptoms following exposure to lipopolysaccharides. Conclusion: The data highlight Klf4 as an essential MCPIP1-dependent modulator of innate immunity that protects against excessive and self-destructive inflammation.

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Section: Discussionmentioning

confidence: 99%

Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6

Jia

Han

et al. 2018

Cell Physiol Biochem

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“…KLF4 was extensively studied particularly after 2006, since it was one of four factors required for pluripotent stem cells induction [125]. KLF4 is upregulated in macrophages in response to IL-4 in both human and mice [23,126]. KLF4 and STAT6 activate each other, then activated KLF4 induces RNase and deubiquitinase activities of monocyte chemoattractant protein induced protein (MCPIP), which stimulates reactive oxygen species production.…”

Section: Krüppel-like Factor 4 (Klf4)mentioning

confidence: 99%

Alternatively activated macrophages; a double-edged sword in allergic asthma

et al. 2020

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Background: Macrophages are heterogenous phagocytic cells with an important role in the innate immunity. They are, also, significant contributors in the adaptive immune system. Macrophages are the most abundant immune cells in the lung during allergic asthma, which is the most common chronic respiratory disease of both adults and children. Macrophages activated by Th1 cells are known as M1 macrophages while those activated by IL-4 and IL-13 are called alternatively activated macrophages (AAM) or M2 cells. AAM are subdivided into four distinct subtypes (M2a, M2b, M2c and M2d), depending on the nature of inducing agent and the expressed markers. Body: IL-4 is the major effector cytokine in both alternative activation of macrophages and pathogenesis of asthma. Thus, the role of M2a macrophages in asthma is a major concern. However, this is controversial. Therefore, further studies are required to improve our knowledge about the role of IL-4-induced macrophages in allergic asthma, through precisive elucidation of the roles of specific M2a proteins in the pathogenesis of asthma. In the current review, we try to illustrate the different functions of M2a macrophages (protective and pathogenic roles) in the pathogenesis of asthma, including explanation of how different M2a proteins and markers act during the pathogenesis of allergic asthma. These include surface markers, enzymes, secreted proteins, chemokines, cytokines, signal transduction proteins and transcription factors. Conclusions: AAM is considered a double-edged sword in allergic asthma. Finally, we recommend further studies that focus on increased selective expression or suppression of protective and pathogenic M2a markers.

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“…Increased numbers of M2 than M1 macrophages have been found in some studies to correlate with graft-loss [99]. KLF4 expression in increased in the InstaScore, and interestingly this gene plays a key role to polarize macrophage into the M2 subset [100], which undertake host defense and wound healing/tissue remodeling tasks [101] and thus can be found to be enriched in renal fibrosis [102].In the AR bopsies in this study, as expected, M1 macrophage signatures were higher in AR [103]. Thus, the macrophage subsets show a dynamic state of skewing the preponderance of M2 to M1 macrophages in the process of immunological priming from pre-AR and full blown AR, and the InstaScore uncovers the state of AR priming or pre-AR in histologically and clinically stable kidney transplants, further highlighting the value of identifying hSTA grafts that are thus at greater risk of AR over time.…”

Section: Discussionmentioning

confidence: 92%