The Sterile Inflammatory Response

Rock, Kenneth L.; Latz, Eicke; Ontiveros, Fernando; Kono, Hajime

doi:10.1146/annurev-immunol-030409-101311

Cited by 756 publications

(701 citation statements)

References 117 publications

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“…The infiltrating mobile cells may also cause tissue destruction. It is worth emphasizing at this point that neutrophils (granulocytes) are far more tissue destructive than macrophages [6] especially when the latter are in a M2-polarised state (CD163 positive) which has been linked to tissue repair. Interestingly, the microglia in the Parkinsonian substantia nigra show this phenotype [7].…”

Section: Classical Inflammationmentioning

confidence: 99%

“…The fundamental processes that give rise to the cardinal symptoms and signs of classical inflammation (Celsus) are centered on and result from changes in the local vasculature [4,6]. In other words, it is the vasculature where the actual inflammation begins with the consequence that every inflammatory process is predominantly if not exclusively interstitial.…”

Section: Classical Inflammationmentioning

confidence: 99%

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Role of microglia in CNS inflammation

2011

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There is increasing confusion about the meaning of the terms inflammation, neuroinflammation, and microglial inflammation. We aim in this review to achieve greater clarity regarding these terms, which are essential for our understanding of the role of microglia in CNS inflammatory conditions. The important concept of sterile inflammation is explained against the backdrop of classical inflammation, and its key differences from what researchers refer to when they use the terms neuroinflammation and microglial inflammation are illustrated. We propose to replace the term “neuroinflammation” with “microglial activation” or “CNS pseudo‐inflammation”, if microglial activation does not suffice. In addition, we recommend abandoning the terms “microglial inflammation” and “inflamed microglia” because of the lack of a clear concept behind them.

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Section: Classical Inflammationmentioning

confidence: 99%

Section: Classical Inflammationmentioning

confidence: 99%

Role of microglia in CNS inflammation

2011

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“…5 In fact, necrosis-derived products, including adenosine triphosphate, mitochondrial DNA (mitDNA; unmethylated CpG motifs), and formyl peptides, may activate their innate immunity receptors in resident and parenchymal cells (e.g., P 2 X 7 , Toll-like receptor 9 [TLR9], and formyl peptide receptor 1 [FPR1], respectively), amplifying the inflammatory response. 6 Notably, during severe organ injury, release of necrotic products to the systemic circulation initiates a ''septic-like'' status and remote organ injury, which was previously observed in patients after severe trauma. 7 In this context, a similar situation might be occurring during acute liver injury, which would explain the systemic inflammatory response that ALF patients display.…”

mentioning

confidence: 94%

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

Marques¹,

Amaral²,

Pires³

et al. 2012

Hepatology

290

269

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Acetaminophen (APAP) is a safe analgesic and antipyretic drug. However, APAP overdose leads to massive hepatocyte death. Cell death during APAP toxicity occurs by oncotic necrosis, in which the release of intracellular contents can elicit a reactive inflammatory response. We have previously demonstrated that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaborate to guide neutrophils to sites of liver necrosis by CXC chemokine receptor 2 (CXCR2) and formyl peptide receptor 1 (FPR1), respectively. Here, we investigated the role of CXCR2 chemokines and mitochondrial products during APAP-induced liver injury and in liver neutrophil influx and hepatotoxicity. During APAP overdose, neutrophils accumulated into the liver, and blockage of neutrophil infiltration by anti-granulocyte receptor 1 depletion or combined CXCR2-FPR1 antagonism significantly prevented hepatotoxicity. In agreement with our in vivo data, isolated human neutrophils were cytotoxic to HepG2 cells when cocultured, and the mechanism of neutrophil killing was dependent on direct contact with HepG2 cells and the CXCR2-FPR1-signaling pathway. Also, in mice and humans, serum levels of both mitochondrial DNA (mitDNA) and CXCR2 chemokines were higher during acute liver injury, suggesting that necrosis products may reach remote organs through the circulation, leading to a systemic inflammatory response. Accordingly, APAP-treated mice exhibited marked systemic inflammation and lung injury, which was prevented by CXCR2-FPR1 blockage and Toll-like receptor 9 (TLR9) absence (TLR9 2/2 mice). Conclusion: Chemokines and mitochondrial products (e.g., formyl peptides and mitDNA) collaborate in neutrophil-mediated injury and systemic inflammation during acute liver failure. Hepatocyte death is amplified by liver neutrophil infiltration, and the release of necrotic products into the circulation may trigger a systemic inflammatory response and remote lung injury.

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“…This ischemic cascade results in loss of cellular integrity and subsequent cellular demise by necrosis or apoptosis [1]. The dying cells and debris elicit sterile inflammation, an inflammatory response in the absence of microbes, in the ischemic brain [2]. Damage-associated molecular patterns (DAMPs), which include modified or oxidized lipid species, cytoplasmic proteins, DNA, RNA, and modified extracellular matrix components, are released from the intracellular compartment at the time of cell demise, triggering stroke-induced inflammation [3,4].…”

Section: Introductionmentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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The Sterile Inflammatory Response

Cited by 756 publications

References 117 publications

Role of microglia in CNS inflammation

Role of microglia in CNS inflammation

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

Microglia and Monocyte-Derived Macrophages in Stroke

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