Emerging roles of the complement system in host–pathogen interactions

Sahu, Sanjaya Kumar; Kulkarni, Devesha H.; Ozantürk, Ayşe Naz; Ma, Lina; Kulkarni, Hrishikesh S.

doi:10.1016/j.tim.2021.09.002

Cited by 21 publications

(20 citation statements)

References 101 publications

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“…Immune resistance is the host’s ability to eradicate pathogens, whereas tissue resilience is the ability of the lung to withstand the deleterious consequences of infection and inflammation ( 1 , 5 ). The complement system is a family of immune proteins that facilitate immune resistance by attacking microbes to decrease pathogen burden ( 6 , 7 ). The cascade can be activated by multiple arms such as the classical, lectin, or alternative pathway, and each of them plays important roles in host defense ( 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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The complement component C3 is a fundamental plasma protein for host defense, produced largely by the liver. However, recent work has demonstrated the critical importance of tissue-specific C3 expression in cell survival. Here, we analyzed the effects of local versus peripheral sources of C3 expression in a model of acute bacterial pneumonia induced by Pseudomonas aeruginosa . Whereas mice with global C3 deficiency had severe pneumonia-induced lung injury, those deficient only in liver-derived C3 remained protected, comparable to wild-type mice. Human lung transcriptome analysis showed that secretory epithelial cells, such as club cells, express high levels of C3 mRNA. Mice with tamoxifen-induced C3 gene ablation from club cells in the lung had worse pulmonary injury compared with similarly treated controls, despite maintaining normal circulating C3 levels. Last, in both the mouse pneumonia model and cultured primary human airway epithelial cells, we showed that stress-induced death associated with C3 deficiency parallels that seen in Factor B deficiency rather than C3a receptor deficiency. Moreover, C3-mediated reduction in epithelial cell death requires alternative pathway component Factor B. Thus, our findings suggest that a pathway reliant on locally derived C3 and Factor B protects the lung mucosal barrier.

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Section: Introductionmentioning

confidence: 99%

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

et al. 2023

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“…The traditionally understood roles of complement in innate immunity take place in the extracellular environment, directly opsonizing and even lysing some pathogens via the action of C3 deposition and formation of the terminal membrane attack complex 1 but also acting as a danger sensing mechanism, transmitting signals to cells via cell‐surface receptors of activated complement components 2 . While these functions have largely been attributed to circulating complement proteins secreted mainly from the liver, it has been recognized that local expression of complement proteins can also have an important role in tissues, 3 for example, in infection 4,5 and in complement‐dependent pathologies 6–8 . The discovery that some cell types express multiple complement proteins required for complete activation pathways, leading to spontaneous activation, also opened the possibility for autocrine complement activation playing roles in cellular homeostasis, activation, and inflammation 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Intracellular complement: Evidence, definitions, controversies, and solutions

King

Blom

2022

Immunological Reviews

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The traditionally understood roles of complement in innate immunity take place in the extracellular environment, directly opsonizing and even lysing some pathogens via the action of C3 deposition and formation of the terminal membrane attack complex 1 but also acting as a danger sensing mechanism, transmitting signals to cells via cell-surface receptors of activated complement components. 2 While these functions have largely been attributed to circulating complement proteins secreted mainly from the liver, it has been recognized that local expression of complement proteins can also have an important role in tissues, 3 for example, in infection 4,5 and in complement-dependent pathologies. [6][7][8] The discovery that some cell types express multiple complement proteins required for complete activation pathways, leading to spontaneous activation, also opened the possibility for autocrine complement activation playing roles in cellular homeostasis, activation, and inflammation. 9,10 For example, more recently, cell-intrinsic C3 expression in fibroblasts has been shown to play an important role in priming tissue sites for inflammation. 11 In autoinflammatory disease, repeated attacks can increase in severity. It was shown that mice injected at the same site with identical doses of sterile inflammatory danger-or pathogenassociated molecular patterns (DAMPs or PAMPs) suffered increasing levels of inflammation, while injection at different sites did not. This was not dependent on the adaptive immune system, as shown using SCID and RAG1-KO mice, but was dependent on C3, as shown using C3-KO mice. In addition, adoptive transfer of exposed fibroblasts from WT but not C3-KO mice "primed" the recipient site for increased inflammation, indicating the importance of fibroblastexpressed C3 in this priming process. This detailed and clear study indicates a role for local, or cell-intrinsic C3 in fibroblasts in sterile inflammation. The exact function of C3 was not however defined,

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“…C3a can activate the C3a receptor (C3aR) on cells inducing either pro-or anti-inflammatory responses (13,16,17). Certain complement proteins, including C3, also exist intracellularly in T lymphocytes, serving as a defense system against intracellular pathogen invasion (18,19). Furthermore, intracellular C3 is closely linked to vital metabolic pathways in T cells and activation of intracellular C3aR in lysosomes by C3a has been suggested to signal via the mammalian target of rapamycin (mTOR) (4,20,21).…”

Section: Introductionmentioning

confidence: 99%

Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis

et al. 2022

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The innate immune system is rapidly activated during myocardial infarction and blockade of extracellular complement system reduces infarct size. Intracellular complement, however, appears to be closely linked to metabolic pathways and its role in ischemia-reperfusion injury is unknown and may be different from complement activation in the circulation. The purpose of the present study was to investigate the role of intracellular complement in isolated, retrogradely buffer-perfused hearts and cardiac cells from adult male wild type mice (WT) and from adult male mice with knockout of complement component 3 (C3KO). Main findings: (i) Intracellular C3 protein was expressed in isolated cardiomyocytes and in whole hearts, (ii) after ischemia-reperfusion injury, C3KO hearts had larger infarct size (32 ± 9% in C3KO vs. 22 ± 7% in WT; p=0.008) and impaired post-ischemic relaxation compared to WT hearts, (iii) C3KO cardiomyocytes had lower basal oxidative respiration compared to WT cardiomyocytes, (iv) blocking mTOR decreased Akt phosphorylation in WT, but not in C3KO cardiomyocytes, (v) after ischemia, WT hearts had higher levels of ATP, but lower levels of both reduced and oxidized nicotinamide adenine dinucleotide (NADH and NAD+, respectively) compared to C3KO hearts. Conclusion: intracellular C3 protected the heart against ischemia-reperfusion injury, possibly due to its role in metabolic pathways important for energy production and cell survival.

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Emerging roles of the complement system in host–pathogen interactions

Cited by 21 publications

References 101 publications

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

Lung epithelial cell–derived C3 protects against pneumonia-induced lung injury

Intracellular complement: Evidence, definitions, controversies, and solutions

Intracellular Complement Component 3 Attenuated Ischemia-Reperfusion Injury in the Isolated Buffer-Perfused Mouse Heart and Is Associated With Improved Metabolic Homeostasis

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