Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis

Weindel, Chi G; Martinez, Eduardo L.; Zhao, Xiao Li; Mabry, Cory J.; Bell, Samantha L.; Vail, Krystal J.; Coleman, Aja K.; VanPortfliet, Jordyn J.; Zhao, Baoyu; Wagner, Allison R; Azam, Sikander; Scott, Haley M; Li, Pingwei; West, A. Phillip; Karpac, Jason; Patrick, Kristin L.; Watson, Robert O.

doi:10.1016/j.cell.2022.06.038

Cited by 168 publications

(107 citation statements)

References 89 publications

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“…Also, in response to virally infected cells, necroptosis and pyroptosis regulate an intertwined system [63,64]. It has recently been demonstrated that macrophages carrying a Lrrk2G2019S mutation display plasticity between pyroptosis and necroptosis, which is mediated by translocation of cGSDMD to mitochondria to form ROS-releasing pores [65]. The release of mitochondrial ROS was Fig.…”

Section: Discussionmentioning

confidence: 99%

Gasdermin D-deficient mice are hypersensitive to acute kidney injury

et al. 2022

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Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.

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Section: Discussionmentioning

confidence: 99%

Gasdermin D-deficient mice are hypersensitive to acute kidney injury

et al. 2022

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“…It is also possible that other immune sensing pathways contribute to this response, as PMNs lacking MyD88 were still able to upregulate MitROS production in response to infection. One such pathway may be the NLRP3 inflammasome, which has been linked to MitROS in several models [67][68][69]. In summary, it is likely that several pathways are involved in MitROS production by PMNs in response to bacterial infection and future studies will focus on pinpointing all the pathways involved and their kinetics during pneumococcal infection.…”

Section: Plos Pathogensmentioning

confidence: 99%

Mitochondrial ROS production by neutrophils is required for host antimicrobial function against Streptococcus pneumoniae and is controlled by A2B adenosine receptor signaling

et al. 2022

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Polymorphonuclear cells (PMNs) control Streptococcus pneumoniae (pneumococcus) infection through various antimicrobial activities. We previously found that reactive oxygen species (ROS) were required for optimal antibacterial function, however, the NADPH oxidase is known to be dispensable for the ability of PMNs to kill pneumococci. In this study, we explored the role of ROS produced by the mitochondria in PMN antimicrobial defense against pneumococci. We found that the mitochondria are an important source of overall intracellular ROS produced by murine PMNs in response to infection. We investigated the host and bacterial factors involved and found that mitochondrial ROS (MitROS) are produced independent of bacterial capsule or pneumolysin but presence of live bacteria that are in direct contact with PMNs enhanced the response. We further found that MyD88-/- PMNs produced less MitROS in response to pneumococcal infection suggesting that released bacterial products acting as TLR ligands are sufficient for inducing MitROS production in PMNs. To test the role of MitROS in PMN function, we used an opsonophagocytic killing assay and found that MitROS were required for the ability of PMNs to kill pneumococci. We then investigated the role of MitROS in host resistance and found that MitROS are produced by PMNs in response to pneumococcal infection. Importantly, treatment of mice with a MitROS scavenger prior to systemic challenge resulted in reduced survival of infected hosts. In exploring host pathways that control MitROS, we focused on extracellular adenosine, which is known to control PMN anti-pneumococcal activity, and found that signaling through the A2B adenosine receptor inhibits MitROS production by PMNs. A2BR-/- mice produced more MitROS and were significantly more resistant to infection. Finally, we verified the clinical relevance of our findings using human PMNs. In summary, we identified a novel pathway that controls MitROS production by PMNs, shaping host resistance against S. pneumoniae.

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“…Mechanistically, pyroptosis is the dominant response upon caspase-1/4/5/11 activation, which occurs in macrophage and non-macrophage cells, both of which can cleave Gasdermin-D (GSDMD) to mediate pyroptotic cell death accompanied with excessive inflammatory factor release [11][12][13]. Previous studies have indicated that suppressing GSDMD cleavage in macrophages can alleviate inflammation and tissue damage in mice [14,15]. In addition, blocking pro-inflammatory cytokines released from macrophages decreases cardiac inflammation [16].…”

Section: Introductionmentioning

confidence: 99%

NEDD4 ameliorates myocardial reperfusion injury by preventing macrophages pyroptosis

Sun

Cui³

et al. 2023

Cell Commun Signal

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Objectives The inflammatory cascade and cell death post-myocardial ischemia reperfusion (MI/R) are very complex. Despite the understanding that macrophage inflammation has a pivotal role in the pathophysiology of MI/R, the contribution of macrophage inflammatory signals in tailoring the function of vascular endothelium remains unknown. Materials and methods In the present study, we analyzed the effects of NEDD4 on the NLRP3 inflammasome activation-mediated pyroptosis in vitro after an acute pro-inflammatory stimulus and in vivo in a MI/R mouse model. TTC and Evan’s blue dye, Thioflavin S, immunohistochemistry staining, and ELISA were performed in wild-type and NEDD4 deficiency mice. THP-1 cells were transfected with si-NEDD4 or si-SF3A2. HEK293T cells were transfected with NEDD4 or SF3A2 overexpression plasmid. ELISA analyzed the inflammatory cytokines in the cell supernatant. The levels of NEDD4, SF3A2, and NLRP3/GSDMD pathway were determined by Western blot. Protein interactions were evaluated by immunoprecipitation. The protein colocalization in cells was monitored using a fluorescence microscope. Results NEDD4 inhibited NLRP3 inflammasome activation and pyroptosis in THP-1 cells treated with lipopolysaccharide (LPS) and nigericin (Nig). Mechanistically, NEDD4 maintained the stability of NLRP3 through direct interaction with the SF3A2, whereas the latter association with NLRP3 indirectly interacted with NEDD4 promoting proteasomal degradation of NLRP3. Deletion of NLRP3 expression further inhibited the caspase cascade to induce pyroptosis. Interestingly, inhibiting NLRP3 inflammasome activation in THP-1 cells could prevent cardiac microvascular endothelial cells (CMECs) injury. In addition, NEDD4 deficiency decreased animal survival and increased myocardial infarct size, no-reflow area, and promoted macrophages infiltration post-MI/R. Conclusions NEDD4 could be a potential therapeutic target in microvascular injury following myocardial reperfusion.

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Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis

Cited by 168 publications

References 89 publications

Gasdermin D-deficient mice are hypersensitive to acute kidney injury

Gasdermin D-deficient mice are hypersensitive to acute kidney injury

Mitochondrial ROS production by neutrophils is required for host antimicrobial function against Streptococcus pneumoniae and is controlled by A2B adenosine receptor signaling

NEDD4 ameliorates myocardial reperfusion injury by preventing macrophages pyroptosis

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