Akt, mTOR and NF-κB pathway activation in Treponema pallidum stimulates M1 macrophages

Lin, Li‐Rong; Gao, Zhengxiang; Lin, Yong; Zhu, Xiao-Zhen; Liu, Wei; Liú, Dan; Gao, Kun; Tong, Man‐Li; Zhang, Huilin; Liu, Li‐Li; Xiao, Yao; Niu, Jianjun; Fan, Lei

doi:10.1016/j.intimp.2018.03.040

Cited by 28 publications

(22 citation statements)

References 17 publications

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“…The results of our in vitro study showed that T. pallidum induced the polarization of M0 macrophages into M1 macrophages at the early infection phase. Within 12 h of infection, the expression of iNOS, an M1 surface marker, was upregulated, and the expression of CD206, an M2 surface marker, was decreased, which was similar with our previous study [ 3 ]. Moreover, the mRNA and protein expression levels of the M1-associated cytokines IL-1β and TNF-α and of the M2-associated cytokine IL-10 were elevated and reduced, respectively.…”

Section: Discussionsupporting

confidence: 91%

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Treponema pallidum promotes macrophage polarization and activates the NLRP3 inflammasome pathway to induce interleukin-1β production

et al. 2018

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BackgroundThe involvement of inflammasome activation and macrophage polarization during the process of syphilis infection remains unknown. In this study, A series of experiments were performed using human macrophages to research the role of NLRP3 inflammasome regulation in interleukin (IL)-1β production and its influence on macrophage polarization triggered by T. pallidum.ResultsThe results showed that in M0 macrophages treated with T. pallidum, the M1-associated markers inducible nitric oxide synthase (iNOS), IL-1β and TNF-α were upregulated, and the M2-associated markers CD206 and IL-10 were downregulated. In addition, we observed NLRP3 inflammasome activation and IL-1β secretion in T. pallidum-treated macrophages, and the observed production of IL-1β occurred in a dose- and time-dependent manner. Moreover, the secretion of IL-1β by macrophages after T. pallidum treatment was notably reduced by anti-NLRP3 siRNA and caspase-1 inhibitor treatment. NAC, KCl, and CA074-ME treatment also suppressed IL-1β release from T. pallidum-treated macrophages.ConclusionsThese findings showed that T. pallidum induces M0 macrophages to undergo M1 macrophage polarization and elevate IL-1β secretion through NLRP3. Moreover, the process of NLRP3 inflammasome activation and IL-1β production in macrophages in response to T. pallidum infection involves K+ efflux, mitochondrial ROS production and cathepsin release. This study provides a new insight into the innate immune response to T. pallidum infection.

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Section: Discussionsupporting

confidence: 91%

“…In our previous study, we have found that the early inflammatory response to T. pallidum infection is most often attributed to the local innate and adaptive cellular immune responses [ 3 , 4 ]. Macrophages are the major cells in the innate immune response and play a crucial role in the early inflammatory reaction.…”

Section: Discussionmentioning

confidence: 99%

Treponema pallidum promotes macrophage polarization and activates the NLRP3 inflammasome pathway to induce interleukin-1β production

et al. 2018

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“…2D,E). The latter is a transcription factor; its phosphorylation leads to a cascade of pro-inflammatory reactions in bacterially infected MΦ-0 18 . Likewise, the secretion of IL6, tumor-necrosis-factor-alpha (TNFα), and IFNy was found higher in infected PBMΦ-0 (all p < 0.05 vs. CBMΦ-0, Fig.…”

Section: Resultsmentioning

confidence: 99%

Impaired functional capacity of polarised neonatal macrophages

Dreschers

Ohl

Schulte

et al. 2020

Sci Rep

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neonatal sepsis is accompanied by impaired apoptotic depletion of monocytes and macrophages (MΦ), aberrant cytokine production, impaired cell metabolism, and sustained inflammation. Macrophage-colony stimulating factor (M-CSF) triggers the differentiation from monocytes into MΦ (MΦ-0). Interleukin-10 (IL10) and Interferon-gamma (IFNy) further differentiate MΦ subpopulations, the anti-inflammatory MΦ-IL10 and the pro-inflammatory MΦ-ifny subtype. We previously have shown significant differences between adult (PBMΦ) and cord blood (CBMΦ) in the metabolism of all subtypes. To test the hypothesis whether the competence to differentiate monocytes into MΦ-0 and to polarise into MΦ-ifny and MΦ-IL10 was diminished in CBMΦ as compared to PBMΦ, we polarised monocytes by cultivation with M-CSF for 72 h, followed by stimulation with IFNy or IL10, for 48 h. After flow cytometry based immunotyping, we tested four functions: Phagocytosis of GFP-E. coli, uptake of erythrocytes, t-cell proliferation, induction of regulatory t-cells as well as phosphorylation analysis of AKT and STAT1/STAT3. Phosphorylation of STAT-1 and STAT-3, obligatory to differentiate into MΦifnγ, MΦ-0 and MΦ-IL10, was found to be aberrant in CBMΦ. Whereas infected MΦ-0 showed identical phagocytic indices and intracellular degradation, TLR4-expression, NFkB up-regulation, IL10-, IL6-, and tnfα production of CBMΦ-0 were reduced. In addition, the capacity to bind aged erythrocytes and the consecutive IL10 production was lower in CBMΦ-IL10. Polarised PBMΦ-IFNy and PBMΦ-IL10 expressed higher levels of co-stimulatory receptors (CD80, CD86), had a higher capacity to stimulate T-cells and induced higher amounts of regulatory t-cells (all p < 0.05 vs. corresponding CBMΦ). Hypoxia-induciblefactor-1α (HIF-1α) was stronger expressed in CBMΦ-IFNy and upregulated in infected CBMΦ-0, whereas heme-oxygenase 1 (HO-1) expression was similar to adult PBMΦ. neonatal MΦ-0, MΦ-ifny and MΦ-IL10 polarisation is impaired with respect to phenotype and functions tested which may contribute to sustained inflammation in neonatal sepsis. Macrophages (MФ) have an extremely broad spectrum of functions in both the induction and resolution of inflammation due to their heterogeneity and plasticity. They are involved in a range of processes, including tissue homeostasis, clearance or pulmonary surfactant as well as inflammation. Deriving from monocytes, they develop into different populations of circulating inflammatory or resident macrophages (MФ) recruited to various tissues. These processes occur in response to inflammation or infection but also in homeostasis in order to replace apoptotic (MФ) 1. The migration of monocytes to the site of infection is crucial 2. After infiltrating the infected tissue they polarise into functional distinguishable MФ. The term "polarisation" instead of differentiation became accepted, since this process depends on the local cytokine milieu and specific microenvironmental cues, and therefore is reversible 3,4. By analogy to T helper cell (Th) nomenclature, MФ ...

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“…In previous studies, we found that macrophages make an essential contribution during the initial T. pallidum invasion. 3,10 Macrophages exhibit high levels of NLRP3 inflammasome activity, 2 release IL-1b, 10 phagocytose T. pallidum 16 their responses to clear spirochetes from infected tissues. However, the mechanism underlying the involvement of macrophage phagocytosis remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…1 Our previous studies showed that macrophages comprise the first line of the host innate immune response and play a crucial role during early syphilis. 2,3 Macrophages have been reported to participate in the eradication of treponemes primarily through phagocytosis of spirochetes. 4 Elucidating the mechanism of the macrophage phagocytic response will improve our knowledge of host defence against T. pallidum.…”

Section: Introductionmentioning

confidence: 99%

Autophagy promotes phagocytosis and clearance of Treponema pallidum via the NLRP3 inflammasome in macrophages

Lin

Zhu

et al. 2020

Acad Dermatol Venereol

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Background Elucidating the mechanism of the macrophage phagocytic response will improve our knowledge of host defence against Treponema pallidum. Objective To explore whether autophagy promotes T. pallidum phagocytosis and clearance via the NLRP3 inflammasome in macrophages. Methods The interactions between autophagy and phagocytosis and the role of NLRP3 in these processes in T. pallidum‐treated macrophages were investigated through experiments using human monocytic cell line (THP‐1)‐derived macrophages. Treponema pallidum clearance after phagocytosis was evaluated by inoculating rabbits with macrophage–treponeme mixtures. Results Activation of autophagy and phagocytosis in T. pallidum‐treated macrophages occurred in a dose‐ and time‐dependent manner. The percentage of spirochete‐positive macrophages (22.34% vs. 70.93%, P < 0.001) and spirochete internalization (MFI: 9.62 vs. 20.33, P < 0.001) were notably reduced by silencing Beclin1. Inoculation of macrophage–treponeme mixtures into rabbits showed a 3.00‐day delay in lesion development (17.55 ± 3.73 vs. 14.55 ± 1.99 days) and decreased lesion numbers [11 (36.7%) vs. 20 (66.7%) of 30; χ2 = 5.406, P = 0.020] in the control compared with the si‐Beclin1 group. Furthermore, silencing NLRP3 decreased the mRNA and protein levels of Beclin‐1 and LC3B [mRNA: 49.86% and 43.02%; protein: 22.31% and 24.24%, respectively, differing significantly from the control group (P < 0.001)] and reduced the percentage of spirochete‐positive macrophages (30.29% vs. 70.53%, P < 0.001) and spirochete internalization (MFI: 9.82 vs. 19.33, P < 0.001). Conclusion Treponema pallidum induces autophagy in macrophages to promote phagocytosis and clearance. The NLRP3 inflammasome modulates autophagy and phagocytosis in vitro. These data may be useful for understanding the host–pathogen relationship and establish the groundwork for strategies to combat syphilis.

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Akt, mTOR and NF-κB pathway activation in Treponema pallidum stimulates M1 macrophages

Cited by 28 publications

References 17 publications

Treponema pallidum promotes macrophage polarization and activates the NLRP3 inflammasome pathway to induce interleukin-1β production

Treponema pallidum promotes macrophage polarization and activates the NLRP3 inflammasome pathway to induce interleukin-1β production

Impaired functional capacity of polarised neonatal macrophages

Autophagy promotes phagocytosis and clearance of Treponema pallidum via the NLRP3 inflammasome in macrophages

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