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The Mitochondrion - A Trojan Horse That Kicks Off Inflammation?
 
 
  NEJM June 3 2010
 
Angelo A. Manfredi, M.D., and Patrizia Rovere-Querini, M.D., Ph.D.
 
Threats to the integrity of an organism cause inflammation. The response is highly conserved and essential: defective or deregulated inflammation is usually incompatible with survival. However, inflammation is risky. Leukocytes recruited to fight microbes cause collateral damage that is often more severe than that originally triggered by the pathogen. Moreover, inflammation takes place even in patients with sterile tissue injuries such as trauma and ischemia–reperfusion.
 
The price that patients pay for inflammation in these conditions is often high. A recent study by Zhang and colleagues1 reveals details of this exchange. In short, the immune system recognizes mitochondria released from dying tissues as the bacteria they (the mitochondria) once were, and it mobilizes its destructive potential to limit their proliferation and arrest an unlikely invasion. This tragic "misunderstanding" could have a role in several human diseases, leading to inflammation in conditions as clinically diverse as post-traumatic systemic inflammatory response syndrome, myocardial infarction, cerebral ischemia, and systemic and organ autoimmunity.
 
The innate immune system is very effective at recognizing pathogens. This recognition is achieved through the identification of molecular "tags," referred to as pathogen-associated molecular patterns, that "label" microbes and not host cells. Given the enormous evolutionary pressure, it seems likely that these patterns are critical to the ability of the microbe to survive or to infect.2 Examples of pathogen-associated molecular patterns are formyl methionine and formylated bacterial proteins, which are synthesized by bacteria and are potent stimuli for leukocyte attraction and activation. Similarly, unmethylated cytosine–phosphate–guanine (CpG) dinucleotides are common in microbial DNA and elicit inflammatory and immunostimulatory responses.
 
Dedicated pattern-recognition receptors endow immune cells - neutrophils, macrophages, dendritic cells, and mast cells - with the ability to recognize microbes; the intracellular toll-like receptor 9 (TLR9), for example, identifies microbial DNA in the endosomal compartment. Germ-line–encoded pattern-recognition receptors are not clonally distributed. All cells that express them immediately identify pathogen-associated molecular pattern–expressing microbes as a potential threat. They initiate inflammation, secreting cytokines and chemokines, which alert and attract other leukocytes, thus focusing their destructive potential at the site of infection.
 
Mitochondria are membrane-bound organelles that produce energy in virtually all eukaryotic cells. They have evolved from an endosymbiont alpha-proteobacterium (a relative of brucella and rickettsia). Mitochondria have their own DNA, enriched in hypomethylated CpG-containing sequences, which is duplicated when mitochondria divide. The origin of the eukaryotic cell is still controversial, and transitional forms between prokaryotes and eukaryotes have not been persuasively documented.3 The amalgamation of two prokaryotes or the amalgamation of a prokaryote with an eukaryotic precursor cell are possible scenarios. Regardless, the merger would have occurred long before the existence of an immune system, which by definition is a feature that is unique to multicellular organisms.
 
Zhang et al. reason that, by virtue of their evolutionary origin, mitochondria might be recognized by pattern-recognition receptors and thus might initiate inflammation. This event seems unlikely to occur in healthy tissues, in which membrane-bound mitochondria are contained within cells. Zhang et al. detected mitochondrial DNA in the blood of patients with systemic inflammatory response syndrome after major trauma, at concentrations sufficient to activate TLR9 and to phosphorylate the p38 mitogen-activated protein kinase (a signaling molecule that is downstream of TLR9). Moreover, Zhang et al. observed that mitochondrial proteins from human tissues activated the receptor of formyl peptide receptor-1 on neutrophils, resulting in the production of a collagenase that sustains leukocyte migration in peripheral tissues. Intravenous injection of mitochondrial proteins into mice resulted in activation of circulating neutrophils, with random extravasation in peripheral organs such as the liver and lung. Acute lung injury developed in these mice, with the production of tumor necrosis factor {alpha} and interleukin-6 and accumulation of proteins and fluids in the alveolar space (Figure 1). Conversely, neutrophils lost the ability to respond to chemoattractants; this could limit their ability to reach sites of infection, which could contribute to the immune depression associated with systemic inflammatory response syndrome.
 
Figure 1. Mitochondrial Danger Signals.

Mitochondrial molecules share several characteristics with microbial molecules. For example, mitochondrial proteins, like bacterial proteins, are formylated at their amino termini. Zhang et al.1 recently observed that intravenously injecting mitochondrial formylated proteins into mice activates neutrophils in the blood, prompting them to extravasate and migrate into peripheral organs. Sequelae include key features of acute lung injury, such as the release of proteases and other toxic moieties that damage the vessel endothelium, with loss of barrier function and edema. DAMP denotes damage-associated molecular pattern, PAMP pathogen-associated molecular pattern, PMN polymorphonuclear cell, PRR pattern-recognition receptor, and TNF-{alpha} tumor necrosis factor {alpha}.
 
The study by Zhang et al. provides new clues about systemic inflammatory response syndrome in patients with major trauma, a condition that to a large extent has hitherto been unexplained. Key questions remain. Molecular mechanisms other than those described by Zhang et al. may be involved in the inflammatory action of mitochondrial molecules. For example, mitochondrial constituents selectively activate an inflammasome4 that regulates the processing and secretion of interleukin-1 and interleukin-18. This observation suggests a possible link with other sterile inflammatory conditions such autoinflammatory diseases. Moreover, other signals (or damage-associated molecular patterns) provided by dying cells have inflammatory potential.5 Mitochondrial structures released by injured cells possibly prompt inflammation during heart, kidney, or brain ischemia–reperfusion injuries, in which local neutrophil activation and further tissue damage occur when the blood flow is restored. Finally, mitochondria are probably released in patients with infectious disease - in whom substantial cell death takes place - possibly contributing to the molecular pathology of sepsis. Altogether, the identification of mitochondria as instigators of inflammation may lead to a new, intriguing candidate for drug discovery.
 
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
 
Source Information
 
From the Istituto Scientifico San Raffaele and Universitą Vita-Salute San Raffaele, Milan, Italy.
 
References
 
1. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010;464:104-107.
 
2. Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989;54:1-13.
 
3. Davidov Y, Jurkevitch E. Predation between prokaryotes and the origin of eukaryotes. Bioessays 2009;31:748-757.
 
4. Iyer SS, Pulskens WP, Sadler JJ, et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A 2009;106:20388-20393.
 
5. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007;81:1-5.
 
 
 
 
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