Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis

Liu, Yang; Liu, Xing; Li, Fen-Xin; Wang, Na; Ma, Yuze; Li, Jianwei; Wu, Yujing; Ji, Liang; Lei, Yuxin; Wang, Xueyin; Meng, F.; Yang, Yongjun; Li, Guangpeng; Wang, Xiao; Yu, Shui-Xing

doi:10.1016/j.isci.2023.106149

Cited by 3 publications

(4 citation statements)

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“…At present, only a few studies have demonstrated that toll-like receptor 4 accelerates granulopoiesis and enhances host defense against C. perfringens infection [21]. The toxins lecithinase and perfringolysin O of C. perfringens have been found to activate the NLRP3 inflammasome, and NLRP3 deficiency leads to increased host susceptibility to C. perfringens infection [22,23]. Consequently, the need for new preventive and therapeutic strategies has become more urgent.…”

Section: Discussionmentioning

confidence: 99%

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling

Liu,

Zhou,

Lin

et al. 2024

Vet Res

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Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING‑deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.

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Section: Discussionmentioning

confidence: 99%

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling

Liu,

Zhou,

Lin

et al. 2024

Vet Res

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“…Subsequently, we examined the expression of inflammatory factors and found that Aim2 deficiency leads to increased KC production and decreased IL-1β production. Recent studies have shown that inflammasome-activated caspase-1 cleaves inactive precursors of the IL-1 family to generate mature cytokines including IL-1β and IL-18 [10,31]. Accordingly, the inflammasome-dependent caspase-1 cleavage dramatically reduced in the muscle tissue of Aim2 −/− mice following pathogenic C. perfringens infection.…”

Section: Discussionmentioning

confidence: 99%

“…The C. perfringens gas gangrene model was established as previously reported [ 10 ]. Age- and sex-matched mice were inoculated intramuscularly with the log-phase C. perfringens strain CP1 (1 × 10 7 or 5 × 10 7 CFUs per mouse).…”

Section: Methodsmentioning

confidence: 99%

“…PRRs that have been characterized include cytosolic DNA sensors, RIG-I-like receptors, NOD-like receptors, Toll-like receptors, and C-type lectin receptors [ 9 ]. Previously, we have provided evidence that MLKL-NLRP3-extracellular traps and GPR120-NLRP3 signaling axes protect against C. perfringens infection by enhancing bactericidal activity [ 10 , 11 ]. Also, Toll-like receptor 4 signaling contributes to host defense against C. perfringens infection through replenishment of neutrophils and elimination of bacteria [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Absent in Melanoma 2 Mediates Inflammasome Signaling Activation against Clostridium perfringens Infection

Ma,

Lou,

Wang

et al. 2024

IJMS

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Absent in melanoma 2 (AIM2), a key component of the IFI20X/IFI16 (PYHIN) protein family, is characterized as a DNA sensor to detect cytosolic bacteria and DNA viruses. However, little is known about its immunological role during pathogenic Clostridium perfringens (C. perfringens) infection, an extracellular bacterial pathogen. In a pathogenic C. perfringens gas gangrene model, Aim2−/− mice are more susceptible to pathogenic C. perfringens soft tissue infection, revealing the importance of AIM2 in host protection. Notably, Aim2 deficiency leads to a defect in bacterial killing and clearance. Our in vivo and in vitro findings further establish that inflammasome signaling is impaired in the absence of Aim2 in response to pathogenic C. perfringens. Mechanistically, inflammasome signaling downstream of active AIM2 promotes pathogen control. Importantly, pathogenic C. perfringens-derived genomic DNA triggers inflammasome signaling activation in an AIM2-dependent manner. Thus, these observations uncover a central role for AIM2 in host defense and triggering innate immunity to combat pathogenic C. perfringens infections.

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Phagocyte extracellular traps formation contributes to host defense against Clostridium perfringens infection

Liu

Liang

et al. 2023

Cytokine

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Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis

Cited by 3 publications

References 0 publications

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling

STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling

Absent in Melanoma 2 Mediates Inflammasome Signaling Activation against Clostridium perfringens Infection

Phagocyte extracellular traps formation contributes to host defense against Clostridium perfringens infection

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