Classical complement and inflammasome activation converge in CD14highCD16- monocytes in HIV associated TB-immune reconstitution inflammatory syndrome

Lage, Silvia Lucena; Wong, Chun-Shu; Amaral, Eduardo Pinheiro; Sturdevant, Daniel E.; Hsu, Denise C.; Rupert, Adam; Wilson, Eleanor; Qasba, Sarojini S.; Naqvi, Nuha; Laidlaw, Elizabeth; Lisco, Andrea; Manion, Maura; Sereti, Irini

doi:10.1371/journal.ppat.1009435

Cited by 5 publications

(3 citation statements)

References 72 publications

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“…Human blood monocytes are bone marrow-derived cells that circulate in the blood for 1-3 days, and during this time undergo a process of maturation from classical CD14 high CD16 − monocytes (also referred as inflammatory monocytes) into non-classical CD14 low CD16 + group (also known as patrolling monocytes) through the generation of an intermediate monocyte subset (CD14 high CD16 + ) (55,56). These monocyte subsets exhibit very distinct functional roles in a variety of homeostatic and pathological conditions and phenotypic changes or dysregulated activation in the circulating mononuclear phagocyte compartment has been implicated in a range of inflammatory disorders, including COVID-19 (57)(58)(59)(60)(61). We therefore first sought to investigate phenotypic changes in circulating blood monocytes from HCs and COVID-19 patients experiencing mild or moderate-severe disease.…”

Section: Significant Changes In Circulating Monocyte Subsets In Covid...mentioning

confidence: 99%

Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16− Monocytes From COVID-19 Patients

et al. 2022

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The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16− monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1β secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.

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Section: Significant Changes In Circulating Monocyte Subsets In Covid...mentioning

confidence: 99%

Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16− Monocytes From COVID-19 Patients

et al. 2022

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“…Caspase-8 can also be involved in ASC specks within active or inhibited inflammasomes in a context-dependent manner ( 189 , 204 ). ASC speck formation have been observed in immune cells such as monocytes in patients with HIV ( 205 , 206 ), tuberculosis-immune reconstitution inflammatory syndrome ( 207 ), severe COVID-19 ( 208 – 211 ), and primary progressive multiple sclerosis ( 212 ), neutrophils in patients with sepsis ( 213 ), severe COVID-19 ( 214 ), and PAMI syndrome ( 215 ), CD1c + DCs found in human fibrotic kidney tissue ( 216 ), and fibroblasts and CD11c + DCs that are associated with experimental influenza ( 217 ). Intracellular ASC speck formation in neutrophils and macrophages can be observed as early as 4 h after Group B Streptococcus infection, corresponding to an IL-1β peak in splenic tissue ( 217 ).…”

Section: Events Upstream Of Pyroptosis and Cytokine Secretion In Infl...mentioning

confidence: 99%

Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling

Jiang

2023

Front. Immunol.

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Inflammasomes are supramolecular platforms that organize in response to various damage-associated molecular patterns and pathogen-associated molecular patterns. Upon activation, inflammasome sensors (with or without the help of ASC) activate caspase-1 and other inflammatory caspases that cleave gasdermin D and pro-IL-1β/pro-IL-18, leading to pyroptosis and mature cytokine secretion. Pyroptosis enables intracellular pathogen niche disruption and intracellular content release at the cost of cell death, inducing pro-inflammatory responses in the neighboring cells. IL-1β is a potent pro-inflammatory regulator for neutrophil recruitment, macrophage activation, and T-cell expansion. Thus, pyroptosis and cytokine secretion are the two main mechanisms that occur downstream of inflammasome signaling; they maintain homeostasis, drive the innate immune response, and shape adaptive immunity. This review aims to discuss the possible mechanisms, timing, consequences, and significance of the two uncoupling preferences downstream of inflammasome signaling. While pyroptosis and cytokine secretion may be usually coupled, pyroptosis-predominant and cytokine-predominant uncoupling are also observed in a stimulus-, cell type-, or context-dependent manner, contributing to the pathogenesis and development of numerous pathological conditions such as cryopyrin-associated periodic syndromes, LPS-induced sepsis, and Salmonella enterica serovar Typhimurium infection. Hyperactive cells consistently release IL-1β without LDH leakage and pyroptotic death, thereby leading to prolonged inflammation, expanding the lifespans of pyroptosis-resistant neutrophils, and hyperactivating stimuli-challenged macrophages, dendritic cells, monocytes, and specific nonimmune cells. Death inflammasome activation also induces GSDMD-mediated pyroptosis with no IL-1β secretion, which may increase lethality in vivo. The sublytic GSDMD pore formation associated with lower expressions of pyroptotic components, GSDMD-mediated extracellular vesicles, or other GSDMD-independent pathways that involve unconventional secretion could contribute to the cytokine-predominant uncoupling; the regulation of caspase-1 dynamics, which may generate various active species with different activities in terms of GSDMD or pro-IL-1β, could lead to pyroptosis-predominant uncoupling. These uncoupling preferences enable precise reactions to different stimuli of different intensities under specific conditions at the single-cell level, promoting cooperative cell and host fate decisions and participating in the pathogen “game”. Appropriate decisions in terms of coupling and uncoupling are required to heal tissues and eliminate threats, and further studies exploring the inflammasome tilt toward pyroptosis or cytokine secretion may be helpful.

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“…Through these multiple pathways, increased activation of the complement system occurs in PWH, as indicated by the increased levels of the complement cleavage products (179). Interestingly, complement activation increases with disease progression to AIDS, as well as in PWH developing IRIS (180)(181)(182)(183).…”

Section: Hiv/siv-induced Complement Pathway Activationmentioning

confidence: 99%

The Youngbloods. Get Together. Hypercoagulation, Complement, and NET Formation in HIV/SIV Pathogenesis

et al. 2022

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Chronic, systemic T-cell immune activation and inflammation (IA/INFL) have been reported to be associated with disease progression in persons with HIV (PWH) since the inception of the AIDS pandemic. IA/INFL persist in PWH on antiretroviral therapy (ART), despite complete viral suppression and increases their susceptibility to serious non-AIDS events (SNAEs). Increased IA/INFL also occur during pathogenic SIV infections of macaques, while natural hosts of SIVs that control chronic IA/INFL do not progress to AIDS, despite having persistent high viral replication and severe acute CD4+ T-cell loss. Moreover, natural hosts of SIVs do not present with SNAEs. Multiple mechanisms drive HIV-associated IA/INFL, including the virus itself, persistent gut dysfunction, coinfections (CMV, HCV, HBV), proinflammatory lipids, ART toxicity, comorbidities, and behavioral factors (diet, smoking, and alcohol). Other mechanisms could also significantly contribute to IA/INFL during HIV/SIV infection, notably, a hypercoagulable state, characterized by elevated coagulation biomarkers, including D-dimer and tissue factor, which can accurately identify patients at risk for thromboembolic events and death. Coagulation biomarkers strongly correlate with INFL and predict the risk of SNAE-induced end-organ damage. Meanwhile, the complement system is also involved in the pathogenesis of HIV comorbidities. Despite prolonged viral suppression, PWH on ART have high plasma levels of C3a. HIV/SIV infections also trigger neutrophil extracellular traps (NETs) formation that contribute to the elimination of viral particles and infected CD4+ T-cells. However, as SIV infection progresses, generation of NETs can become excessive, fueling IA/INFL, destruction of multiple immune cells subsets, and microthrombotic events, contributing to further tissue damages and SNAEs. Tackling residual IA/INFL has the potential to improve the clinical course of HIV infection. Therefore, therapeutics targeting new pathways that can fuel IA/INFL such as hypercoagulation, complement activation and excessive formation of NETs might be beneficial for PWH and should be considered and evaluated.

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Classical complement and inflammasome activation converge in CD14highCD16- monocytes in HIV associated TB-immune reconstitution inflammatory syndrome

Cited by 5 publications

References 72 publications

Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16− Monocytes From COVID-19 Patients

Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16− Monocytes From COVID-19 Patients

Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling

The Youngbloods. Get Together. Hypercoagulation, Complement, and NET Formation in HIV/SIV Pathogenesis

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