Crystallopathy

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Crystallopathy is a harmful state or disease associated with the formation and aggregation of crystals in tissues or cavities, [1] [2] or in other words, a heterogeneous group of diseases caused by intrinsic or environmental microparticles or crystals, promoting tissue inflammation and scarring. [3]

Contents

Composition

Crystallopathies can be associated with four main kinds of crystalline structures: liquid non-aggregating crystal solutions, amorphous nano-scale solid particles, crystalline micro-scale solid particles, and polycrystalline larger solid structures. They can be composed of various minerals, metabolites, proteins, and microparticles, including the following: [1]

Location

In principle, crystal formation can happen anywhere in the body. Well-known places are excretory organs where concentrations get high easily, like in the biliary and urinary tracts, but crystalline structures are also formed in intracellular and extracellular spaces of tissues, like within the arterial wall in atherosclerosis. [1]

For example, mechanical obstruction by mineral stones causes nephrolithiasis, urolithiasis, cholecystolithiasis, choledocholithiasis, docholithiasis, and sialolithiasis, and acute inflammation caused by crystals in joints causes gout and pseudogout. [1]

Renal diseases are also common in crystallopathies, including: [1]

Mechanisms

Local supersaturation is a common trigger of crystallization, and when the nucleus of the crystalline structure is formed, crystals can self-perpetuate and cause more crystallization and aggregation. Main mechanisms by which the formed crystals and aggregates cause pathological states and ultimately disease are acute necroinflammation, chronic tissue remodelling, and mechanical obstruction. [1]

Necroinflammation is an autoamplifying process where crystals are toxic to cells (cytotoxicity) and cause cell death (necrosis and regulated cell death) and a local and systemic inflammatory response. Cytotoxicity includes actin depolymerization, free radical and reactive oxygen species synthesis, and autophagy. Crystals can also directly activate inflammation via Mincle receptors, calcium and potassium signalling, calpains, cathepsin beta, proteases, and NLPR3 inflammasomes. Cells undergo cell death via three main mechanisms: nectoptosis via RIPK1, FADD, RIPK3, and MLKL, ferroptosis via GPX4 suppression, system Xc suppression, and NAPDH loss, as well as apoptosis via RIPK1 and caspase 8. These distressed cells then excrete alarmins, proteases, and damage-associated molecular patterns including HMGB1, histones, mitochondrial DNA, demethylated DNA and RNA, ATP, uric acid, and double-stranded DNA, which further activates Toll-like receptors and inflammasomes. Finally, this activates the inflammatory response including the release of pro-inflammatory interleukin 1 alpha, interleukin 1 beta, cytokines, kinins, lipid inflammatory mediators, complement system activation, vasodilation, an increase in endothelial permeability and leukocyte influx, and pain. [1]

Macrophages are key cells that try to remove crystals from tissues by phagocytosis. As part of the inflammatory response, they undergo polarization into a pro-inflammatory state called M1. Macrophages can ingest particles at most a few microns in diameter. If digestion of the crystalline material fails in the lysosomes however, macrophages undergo autophagy, form foam cells and giant cells, and try to do extracellular digestion in a process called frustrated phagocytosis. [1]

Crystals do not always cause acute inflammation but instead lead to chronic tissue remodelling. This process is possible because crystals get shielded from pro-inflammatory processes by compartmentalization (e.g. granuloma formation, fibrosis, and wound-healing) or molecular coating, or because inflammatory responses are suppressed with direct anti-inflammatory signalling (e.g. CLEC12A and NETosis). [1]

Crystals can attach to membranes via annexin II, CD44, and osteopontin. [1]

Interventions

The most straightforward treatment of crystallopathies would be dissolving the crystals. Crystal dissolvents have been under research, for example with cyclodextrin in atherosclerosis. Another approach would be to modify the inflammatory pathways common for crystallopathies with treatments such as IL-1a and IL-1b antagonists, NLRP3-antagonists, or blockers of ferroptosis and necroptosis. For protein-based crystallopathy, pharmacologic chaperones, protein stabilizing small molecules, and protein refolding agents have been under consideration. [1]

Related Research Articles

Inflammation Physical effects resulting from activation of the immune system

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

Granuloma Medical condition

A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectious organisms including bacteria and fungi, as well as other materials such as foreign objects, keratin, and suture fragments.

Striated muscle tissue Muscle tissue with repeating functional units called sarcomeres

Striated muscle tissue is a muscle tissue that features repeating functional units called sarcomeres. The presence of sarcomeres manifests as a series of bands visible along the muscle fibers, which is responsible for the striated appearance observed in microscopic images of this tissue. There are two types of striated muscle:

Kupffer cell

Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in the liver within the lumen of the liver sinusoids and are adhesive to their endothelial cells which make up the blood vessel walls. Kupffer cells comprise the largest population of tissue-resident macrophages in the body. Gut bacteria, bacterial endotoxins, and microbial debris transported to the liver from the gastrointestinal tract via the portal vein will first come in contact with Kupffer cells, the first immune cells in the liver. It is because of this that any change to Kupffer cell functions can be connected to various liver diseases such as alcoholic liver disease, viral hepatitis, intrahepatic cholestasis, steatohepatitis, activation or rejection of the liver during liver transplantation and liver fibrosis. They form part of the mononuclear phagocyte system.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

Innate immune system One of the two main immunity strategies

The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

Urinary cast Cylindrical protein structure in urine in certain disease states

Urinary casts are microscopic cylindrical structures produced by the kidney and present in the urine in certain disease states. They form in the distal convoluted tubule and collecting ducts of nephrons, then dislodge and pass into the urine, where they can be detected by microscopy.

Feline lower urinary tract disease Any disorder affecting the bladder or urethra of cats

Feline lower urinary tract disease (FLUTD) is a generic category term to describe any disorder affecting the bladder or urethra of cats.

Phosphate nephropathy or nephrocalcinosis is an adverse renal condition that arises with a formation of phosphate crystals within the kidney's tubules. This renal insufficiency is associated with the use of oral sodium phosphate (OSP) such as C.B. Fleet's Phospho soda and Salix's Visocol, for bowel cleansing prior to a colonoscopy.   

Bladder stone (animal)

Bladder stones or uroliths are a common occurrence in animals, especially in domestic animals such as dogs and cats. Occurrence in other species, including tortoises, has been reported as well. The stones form in the urinary bladder in varying size and numbers secondary to infection, dietary influences, and genetics. Stones can form in any part of the urinary tract in dogs and cats, but unlike in humans, stones of the kidney are less common and do not often cause significant disease, although they can contribute to pyelonephritis and chronic kidney disease. Types of stones include struvite, calcium oxalate, urate, cystine, calcium phosphate, and silicate. Struvite and calcium oxalate stones are by far the most common.

NLRP3

NLR family pyrin domain containing 3 (NLRP3), is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe deposition of calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate. It may cause acute kidney injury. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification in radiology. It is caused by multiple different conditions and is determined progressive kidney dysfunction. These outlines eventually come together to form a dense mass. During its early stages, nephrocalcinosis is visible on x-ray, and appears as a fine granular mottling over the renal outlines. It is most commonly seen as an incidental finding with medullary sponge kidney on an abdominal x-ray. However, it may be severe enough to cause renal tubular acidosis or even end stage kidney disease, due to disruption of the kidney tissue by the deposited calcium.

Allograft inflammatory factor 1 Protein-coding gene in the species Homo sapiens

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Inflammasome

Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of Gasdermin-D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

Necroptosis Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier.

Dapansutrile Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by a dysfunction of the innate immune system.They are characterised by a perdiodic or chronic systemic inflammation usually without the involvement of adaptive immunity.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Mulay, Shrikant R.; Longo, Dan L.; Anders, Hans-Joachim (2016). "Crystallopathies". New England Journal of Medicine. 374 (25): 2465–2476. doi:10.1056/NEJMra1601611. ISSN   0028-4793. PMID   27332905.
  2. ↑ Mulay, Shrikant R.; Steiger, Stefanie; Shi, Chongxu; Anders, Hans‐Joachim (2020). "A guide to crystal‐related and nano‐ or microparticle‐related tissue responses". The FEBS Journal. 287 (5): 818–832. doi: 10.1111/febs.15174 . ISSN   1742-464X. PMID   31829497.
  3. ↑ Steiger, Stefanie; Grill, Julia Felicitas; Ma, Qiuyue; Bäuerle, Tobias; Jordan, Jutta; Smolle, Michaela; Böhland, Claudia; Lech, Maciej; Anders, Hans-Joachim (2018). "Anti-Transforming Growth Factor β IgG Elicits a Dual Effect on Calcium Oxalate Crystallization and Progressive Nephrocalcinosis-Related Chronic Kidney Disease". Frontiers in Immunology. 9: 619. doi: 10.3389/fimmu.2018.00619 . ISSN   1664-3224. PMC   5884871 . PMID   29651290.
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