• fibrosis;
  • wound healing;
  • NLRP3 inflammasome;
  • IL-1β;
  • IL-18


  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References

Inflammasome signalling and downstream cytokine responses mediated by the inflammasome have been found to play an important role, not only in wound healing but also in fibrosis. The inflammasome regulates the secretion of IL-1β and IL-18 cytokines, and both are critical for the repair of damaged tissue and play a role in fibrosis. However, what dictates the fine balance between normal wound healing versus fibrosis is yet to be fully elucidated. Further investigations into the role of the inflammasomes in these pathologies will be important for the discovery of novel therapeutics that can abrogate fibrosis or promote wound healing in chronic disease.Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References

Wound healing is a normal event and is required for the healing of damaged tissues and requires the deposition of collagen into the tissues, whereas fibrosis is the replacement of normal structural elements of the tissue with excessive accumulation of scar tissue comprised of distorted collagens. IL-1β and IL-18 are required during wound healing and fibrosis and the downstream signalling mediated by these cytokines regulates the deposition of collagen. Wound healing in the absence of underlying disease is transient and the cytokine signalling is strongly regulated, inducing controlled collagen deposition. In contrast, fibrosis is a chronic uncontrolled pathology in which cytokines are constantly being produced to drive the continuous production of collagens. The resulting fibrotic scar tissue will eventually impede the normal functioning of the organ and can lead to morbidity and mortality.

Wound healing and fibrosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References

Wound healing

Wound healing is a dynamically complex but ordered process that is tightly regulated, comprising an inflammatory stage, a proliferative stage and a remodelling stage (reviewed in [1-3]). The majority of wounds are relatively minor and are usually closed within 12–14 days; however, the complete resolution of larger wounds may take several months to a year. In normal skin, the epidermal and dermal layers exist in homeostasis, protecting the body from any external insults and pathogens that make up the microbiome of the skin. Any trauma resulting in a breach of this protective barrier will induce wound healing [3].

The inflammatory phase occurs within minutes after the initial injury, due to the tissue damage, cell death at the site, changes in mechanical tension and release of endogenous antigens and alarmins, such as ADP and ATP. The clotting process occurs to stem the loss of blood and platelets caught in the clot secrete thrombin and fibrin, which further promotes the clotting cascade in addition to the recruitment of inflammatory cells. The inflammatory phase can last for up to 4 days post-injury (reviewed in [1, 3]). Large numbers of neutrophils, polymorphonuclear cells and macrophages enter the wound bed to phagocytose debris and microorganisms found within the injured tissue [2]. The recruitment of inflammatory cells to the wound is necessary for normal wound healing and induces the release of epidermal growth factor, transforming growth factor-β1 (TGFβ1) and fibroblast growth factor; and these growth factors induce the recruitment, maturation and proliferation of fibroblasts, fibrocytes and myofibroblasts, resulting in the secretion of high levels of collagens and extracellular matrix molecules [4]. During the proliferative stage, tissue granulation starts and the original fibrin clot is replaced with a temporary matrix, composed primarily of collagen, fibronectin and hyaluronic acid, which is slowly replaced by a stronger extracellular matrix in the remodelling phase at later stages [1-3]. Keratinocytes proliferate and migrate along the temporary granulated tissue, closing the wound surface and providing additional protection to the wound and laying down laminin and type IV collagen [1, 3]. Endothelial cells promote angiogenesis and reoxygenation of the wound [3].

During the remodelling stage there is contraction and maturation of the extracellular matrix and this is mediated by myofibroblasts [5, 6] that induce contraction of the wound [7, 8], and this process can last for days or from several weeks to up to 1 year, depending on the severity of the wound. During this process, the myofibroblasts initially secrete type III collagen but, as the wound healing progresses, they produce more of the stable type I collagen to reinforce the wound and provide strength to the extracellular matrix [9, 10]. The collagen fibres are then reorganized and crosslinked, increasing fibre strength in the wound.


In a recent review by Thomas Wynn [11], it was estimated that approximately 45% of all deaths in the Western world can be attributed to some form of fibrosis resulting from the increased accumulation of collagens and extracellular matrix molecules in the internal organs or tissues. Fibroblasts are the prime cells that secrete extracellular matrix, and fibrosis can be manifested in any organ that contains these cells, including lungs, kidney, liver, skin and heart. Fibrosis can affect a single organ or be systemic, affecting numerous organs. The causative agent triggering the development of fibrosis is more often than not unknown; however, in some cases fibrosis can be attributed to pathogens [12, 13] or inert substances, such as radiation [14], silica, asbestos, cigarette smoke (reviewed in [15]) and other chemicals [16]. Currently, the FDA has not approved any drug treatment for fibrosis, as all have failed clinical trials.

It is has been proposed that fibrosis occurs due to the dysregulation of the wound-healing process at either the proliferative or remodelling stages, or if the irritant persists in the tissues to continually drive the process [17]. Fibrosis can occur with or without inflammation. It is often refractory to treatment and carries a high mortality rate.

The inflammasomes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References

The innate immune response comprising the inflammasomes is one of the first lines of defence against tissue damage and pathogen invasion. The inflammasome mediates the activation and recruitment of inflammatory cells to the site of danger through the release of proinflammatory factors. The inflammasomes are capable of recognizing endogenous and exogenous alarm signals arising from intracellular or extracellular stressors. Endogenous stressors that are known to activate the inflammasome include specific chemical alarm signals, such as uric acid [18, 19], ATP [20], potassium efflux from the cell [21] and the newly identified endogenous peptide, acALY18 [22, 23]. Exogenous stressors include pathogen-associated molecular patterns derived from a diverse range of conserved molecular motifs that are unique to bacteria, viruses and parasites [24-30], from exogenous chemicals [31, 32] or ultraviolet light [33]. The mechanism by which the alarm signal is detected is yet to be fully elucidated for the majority of inflammasomes. During inflammasome activation apoptosis speck-like protein containing a caspase activation and recruitment domain (CARD) (ASC) moves from the nucleus and assembles into the inflammasome complex recruiting procaspase-1. The resulting association of these proteins causes the cleavage and activation of caspase-1. Once caspase-1 is activated, it is then able to cleave a number of key pro-inflammatory cytokines, such as IL-1β and IL-18 [34, 35].

Inflammasomes are not restricted to inflammatory cells, such as monocytes/macrophages [36] or T cells [37], but are functional in a broad range of non-immune cells, such as epithelial cells [38, 39], hepatic stellate cells [40], myofibroblasts [41] and keratinocytes [38, 42]. We propose that activation of the inflammasome in non-immune cells often precedes inflammasome activation in immune cells, and the role of the immune cells is to amplify the inflammatory response at sites of infection or cellular damage [22].

The NLRP3 inflammasome is the most extensively studied inflammasome and this inflammasome is capable of sensing a wide variety of alarm signals from endogenous and exogenous sources [43]. How the NLRP3 inflammasome can detect such a wide variety of alarm signals is yet to be fully determined. Recently, it was found that the assembly of the NLRP3 inflammasome requires the presence of reactive oxygen species [32] and the positional interaction between the endoplasmic reticulum and mitochondria [44]. Quiescent NLRP3 is localized to the endoplasmic reticulum; however, once the inflammasome is activated, both NLRP3 and ASC redistribute to the perinuclear region of the cell, where they co-localize with the endoplasmic reticulum and mitochondrial organelles [44]. These data suggest that reactive oxygen species and mitochondrial signalling may play a significant role in the assembly and activation of the NLRP3 inflammasome; however, whether reactive oxygen species activates other inflammasome platforms is not known.

Assembly and activation of the inflammasome complex leads to the cleavage of caspase-1 (IL-1β converting enzyme/ICE) in a process that is tightly regulated. The active form of caspase-1 is able to cleave a wide variety of protein precursors that do not contain a secretion signalling sequence in a manner that is still not fully elucidated, but appears to occur through an endoplasmic reticulum/Golgi-independent pathway [45, 46] that is now thought to involve autophagy (reviewed in [47]). This secretory pathway utilizes autophagic organelles requiring ATG factors and Golgi reassembly and stacking protein (GRASP)-55 and GRASP-65 [48]. In addition to autophagy regulating the secretion of IL-1β, it also appears that autophagy may regulate the activation of the inflammasome. In our studies, we found that ASC is secreted from activated myofibroblasts at a higher rate than quiescent fibroblasts (unpublished data) and this has been confirmed in other cells [49], suggesting that the inflammasome is secreted in a process that regulates its own activation. Furthermore, once activated, caspase-1 also induces its own secretion [50], possibly by the same autophagic mechanism, and we believe that this may also further regulate the cleavage of proteins that are processed by caspase-1.

The inflammasome regulates the processing of IL-1β and IL-18; cytokines that are critically involved in wound healing and fibrosis

IL-1β and IL-18 belong to the IL-1 family of proteins are processed into mature biologically active proteins when caspase-1 is activated. These proteins then become available for secretion. Numerous other proteins are also processed by caspase-1 [50] and many of these proteins are involved in inflammation [50], the cytoskeleton of the cell [50, 51], glycolysis [51] and mitochondrial function [50].

Depending on the initiating mechanism, activation of the inflammasome can run a well-defined course, with resolution of inflammation and healing of the injury, or be continuous, resulting in chronic disease or fibrosis. As yet the acute response to an initiating event (tissue injury), with resolution of the injury versus a chronic response leading to unresolved disease and fibrosis, is not known. We speculate that in acute disease, the injury is able to be completely resolved, with clearance of the initiating signal (pathogen, virus, chemical, etc.), whereas in chronic disease leading to fibrosis the resulting pathogen or irritant is unable to be cleared, leading to continuous inflammasome activation and IL-1β and IL-18 processing.

IL-1β in fibrosis and wound healing

The role of IL-1β in fibrosis and wound healing is now becoming significantly apparent, and recent studies have elucidated some of the downstream mechanisms that result in the induction of collagen. IL-1β can directly stimulate collagen secretion by fibroblasts in a dose-dependent manner [52] and the transient over-expression of IL-1β by airway epithelial cells was found to increase TGFβ1 and collagen deposition in the lung [53].

The transient expression of IL-1β is important for normal wound healing; however, chronic expression of IL-1β appears to mediate fibrosis. In normal wound healing, IL-1β secretion is found to peak at day 1 and declines during days 3–7 post-injury [54]. Thomay et al [55] employed a deep incisional wound-healing model and found that mice deficient in the IL-1 receptor had improved wound healing, with less fibrosis, and had more collagenolytic activity. The wound fluids contained less TGFβ1, IL-6 and vascular endothelial growth factor. They recapitulated this model in wild-type mice and administered Anakinra (IL-1 receptor antagonist) during the wound-healing phase and found that the deep wounds contained less fibrosis [55]. These studies suggest that IL-1 signalling at least in the setting of deep incisional wounds is profibrotic.

The dichotomous role of IL-1β was investigated in studies by Luo et al [56], who demonstrated that a short exposure time of minutes with IL-1β and TGFβ1 on proximal tubular cells inhibited the phosphorylation of Smad3, and this in turn inhibited downstream TGFβ1 signalling. In contrast, they found that the long exposure (24 h) of proximal tubular cells to IL-1β and TGFβ1 increased Smad3 phosphorylation, further enhancing TGFβ1 signalling [56]. Other cells also exhibit similar responses to IL-1β, and exposure of microvascular endothelial cells to IL-1β was found to promote the permanent transformation of these cells into myofibroblasts [57].

IL-18 in fibrosis and wound healing

Few studies have investigated the role of IL-18 in wound healing or fibrosis. IL-18 mRNA is constitutively expressed with low endogenous levels of protein in normal skin and, upon injury, the mRNA is rapidly translated into protein. Like IL-1β, IL-18 protein in wounded skin is transient and peaks at days 5–7 [58]. Immediately after wounding, there is a rapid decrease in IL-18 mRNA in the skin, but this returns to normal levels by day 13, once re-epithelialization is complete [58]. In wound healing, IL-18 induces TGFβ1 [58] and can induce IFNγ secretion by inflammatory cells. Interestingly, the inhibition of IFNγ signalling resulted in improved wound healing compared to wild-type mice [59], suggesting that IFNγ is required for balanced wound healing and that its absence may promote fibrosis.

The dose-dependent addition of IL-18 to fibroblasts increased the expression of type I and type III collagen proteins. Furthermore IL-18 induced collagen gel contraction [60]. IL-18 enhances fibroblast proliferation [60] and is able to induce the expression of α2β1 integrin [60], one of the receptors that binds collagen. IL-18 can also induces osteopontin expression and this protein is associated with fibrosis [61]. Administration of recombinant IL-18 was able to cause myocardial remodelling, leading to interstitial myocardial fibrosis [62]. In contrast, the targeting of IL-18 with Felodipine (Plendil) reduced perivascular fibrosis [63] via a process that blocks calcium channel signalling [64]. Calcium channel signalling has recently been shown to be important for inflammasome activation [65, 66]; therefore, the reduced secretion of IL-18 may in fact be directly due to the inhibition of the inflammasome, rather than the targeting of Felodipine to IL-18.

The NLRP3 inflammasome in wound healing and fibrosis

Not extensively studied in the context of the inflammasome, the process of cellular trauma during an acute injury will activate the inflammasome due to the very fact that endogenous alarm signals will be released from damaged cells (Figure 1). Recently, three studies have come to light that suggest that the NLRP3 inflammasome may play an anti-fibrotic role during infection; however, there is overwhelming evidence to suggest that the NLRP3 inflammasome can drive fibrosis in the right setting. In the first study, it was found that the NLRP3 inflammasome was required to regulate the healing of damaged lung tissues after Influenza A infection and, intriguingly, NLRP3-deficient mice had increased deposition of collagen in the tissues upon infection [67]. The second study reported that IL-1β signalling was required for epithelial repair during Chlamydia pneumoniae infections, and that inhibition of NLRP3 and IL-1 receptor signalling promoted fibrosis during acute lung infection [27]. The final study found that oxidized Streptolysin O promoted wound healing [68-70]. In the context of these studies, pathogens or pathogen-derived products were signalling the inflammasome and thus it is possible that more than one inflammasome could be activated, inciting the inflammatory response and downstream effects that abrogated collagen deposition in the tissues. However, as discussed below, sterile inflammation may be the mechanism that promotes fibrosis via the NLRP3 inflammasome.


Figure 1. Inflammasome activation in stromal cells during wound healing or fibrosis. The mechanisms whereby the inflammasome becomes activated in stromal cells during wound healing or fibrosis will be similar and mediated by damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs) and alarmins. Once the alarm signal has bound and activated the inflammasome, IL-1β and IL-18 will be cleaved by the activated caspase-1 protein, and then secreted. Autocrine signalling by IL-1β and IL-18 will promote the increased gene expression of extracellular matrix molecules, resulting in the deposition of collagens in the tissues. The inflammasome will be transiently activated during wound healing, resulting in the expression of IL-1β and IL-18 that limits collagen deposition in the injured tissue. In contrast, during fibrosis the inflammasome will be chronically activated and this will constantly drive the profibrotic process via IL-1β and IL-18 signalling. We speculate that the alarm signal that drives this process is not neutralized and, as a result, the activated cell continually deposits extracellular matrix into the tissues.

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The involvement of the inflammasome in fibrotic diseases is now being elucidated (Figure 1); however, many studies to date have focused on inflammasome activation in inflammatory cells, rather than the activation of the inflammasome in stromal cells or parenchymal cells. Activation of the inflammasome appears to be involved in many chronic idiopathic diseases in addition to being involved in pathogen recognition or the recognition of cellular alarm signals (now collectively called alarmins), and yet fibrosis is not a generic feature of an activated inflammasome. In fact, fibrosis in the context of inflammasome activation is an exception. We speculate that the resulting fibrosis that is driven by an activated inflammasome could be dependent on a number of factors, including the initiating events leading to inflammasome activation, the specifically activated inflammasome or inflammasome combination, the genetic variations that affect the response of the target cell to the activated inflammasome, inflammasome by-products, such as IL-1β and IL-18, the level of cytokine secreted from the cell, the cell type in which the inflammasome is activated (inflammatory cells versus stromal or parenchymal cells) or the duration of the activation of the inflammasome (transient versus chronic).

Even though stromal cells are not immune cells, activation of these cells is capable of inducing cytokine secretion that promotes downstream recruitment of inflammatory cells, and this can occur by inflammasome activation. Historically, fibroblasts have not been considered central to the immune response, neither have they been considered to be immunologically relevant in infections; however, they can become activated to release of chemokines and cytokines for the recruitment of monocytes and neutrophils to sites when the skin has been breached or infected by a pathogen. Fibroblasts should be considered to be sentinel cells that respond to bacterial products and cellular alarm signals due to tissue damage [71]. Inflammasome activation induces the differentiation of quiescent fibroblasts to myofibroblasts [41]. We hypothesize that it is the continuous dysregulation of the inflammasome that promotes the differentiation of myofibroblasts, leading to excessive extracellular matrix accumulation and resulting in failure of the affected organ. In contrast, in normal wound healing, inflammasome signalling is tightly regulated and, once the wound is closed, the myofibroblasts undergo apoptosis, limiting collagen secretion.

Wound healing

  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References

Inflammatory caspases are important regulatory molecules found in the skin and their activation is involved in many chronic skin diseases [72] and wound healing. In contact hypersensitivity, vessel permeability and oedema is mediated by the local release of IL-1β, and the release of IL-1β often peaks several hours after exposure to the antigen. The release of IL-1β and IL-18 recruits T cells to the dermis and epidermis, resulting in the hypersensitivity seen in the acute inflammatory response of contact dermatitis. Not only is caspase-1 activated, but caspase-4 and caspase-5 are also activated via the inflammasome and are able to process IL-1β. Caspase-1 activity is elevated in psoriasis lesions and in lesional skin regulates the processing of IL-18 [73], and caspase-4 and caspase-5 are detected in psoriatic skin [74]. Caspase-1 also plays a role in nociception and sensitization in incisional wounds [75].

Keratinocytes are a first line of defence against bacterial, viral and chemical insults in the skin and are able to respond to a variety of insults with the activation of inflammasomes. Keratinocytes are a potent source of IL-1β, which is released during cellular stress. UVB induces the activation of the inflammasome by increasing Ca2+ stores to the cytosol, and this promotes the release of IL-1β [49]. NLRP1 and NLRP3 were found to mediate the responses to UVB damage of keratinocytes [49]. Other studies investigating the NLRP3 inflammasome in keratinocytes during contact hypersensitivity demonstrated that this protein was involved in eliciting the early responses to antigens that promote the priming of T cells [76]. Keratinocytes up-regulate the expression of the AIM2 inflammasome as a response to double-stranded DNA and this is able to trigger the strong release of IL-1β [77].


  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References

Current studies corroborate the role of the NLRP3 inflammasome in driving collagen deposition in the tissues and the activation of caspase-1 in wound healing. The initial investigations involving the inflammasome in pulmonary fibrosis were performed by Gasse et al [78]. Mice that were deficient in the ASC protein (apoptosis-associated speck-like protein containing a CARD) had attenuated responses to the profibrotic compound, bleomycin. This suggests that one of the actions of bleomycin is to stimulate the inflammasome, possibly through the mechanism that induces reactive oxygen species and endoplasmic reticulum assembly with mitochondria [44]. In mice that were IL-1 receptor deficient, there were abrogated responses to bleomycin. These findings were further recapitulated by the direct administration of mouse recombinant IL-1β into the lungs of wild-type mice, resulting in marked increase in tissue destruction with inflammation and collagen deposition. In contrast, inhibition of IL-1 signalling with the IL-1 receptor antagonist (Anakinra) limited fibrosis and was more effective than the administration of IL-1β-neutralizing antibodies. This thorough study was able to demonstrate that IL-1β production was dependent on the inflammasome protein ASC [78].

In studies to further elucidate how bleomycin was stimulating the inflammasome, Gasse et al found that uric acid was released into the lung parenchyma when bleomycin was instilled into the lungs [18]. Uric acid is soluble in the cytosol of the cell; however, when it is released by injured cells it precipitates, forming monosodium urate crystals that are microscopic in size, and these crystals stimulate an immune response [79]. Gasse et al [18] speculated that the localized increase in uric acid resulted in the deposition of crystals that cause membrane damage to cells, resulting in the activation of NLRP3 inflammasome and subsequent release of IL-1β. This group further demonstrated that the signalling mediated by uric acid was dependent on the IL-1 receptor and the NLRP3 inflammasome [18], and they suggest an autocrine signalling loop mediating fibrosis. Utilizing the caspase-1 deficient mouse, they were able to demonstrate that caspase-1 was necessary for the profibrotic effect of bleomycin.

Further analysis of uric acid as an alarm signal capable of activating the inflammasome was performed by this same group on a model of elastase-induced emphysema [80]. They demonstrated that alveolar breakdown and the resulting fibrotic phenotype was dependent on an inflammasome requiring ASC and the release of IL-1β. These effects were abrogated by Anakinra [80]. The direct administration of uric acid crystals into murine airways resulted in a transient increase in inhibitors of extracellular matrix degradation, and the administration of elastase into the lung caused the dying cells to release uric acid [18].

The liver can be easily injured by numerous types of insult, including viruses and chemicals. Once injured, the liver can respond to the insults by establishing inflammation leading to fibrosis. Hepatic stellate cells are able to differentiate into myofibroblasts and up-regulate collagen secretion. Activated hepatic stellate cells can phagocytose pathogen and cellular debris, present antigen, express α-smooth muscle actin stress fibres, and migrate [81]. Watanabe et al [40] found that monosodium urate crystals activated the inflammasome, leading to liver fibrosis, and these findings are further suggestive that the inflammasome is an important signalling pathway central to fibrotic diseases. In addition, Gieling et al [82] found that the progression of liver fibrosis was mediated by IL-1α and IL-1β, peaking on day 1, whereas collagen and α-smooth muscle actin peaked at day 3.

We recently reported that the fibrosis in the autoimmune disease systemic sclerosis (SSc; scleroderma) was dependent on the inflammasome [41]. We found that collagen secretion by myofibroblasts could be abrogated if caspase-1 was inhibited and, by inhibiting caspase-1, we found that IL-1β and IL-18 were also inhibited. These data suggest that the release of IL-1β and IL-18 in SSc is mediated by an inflammasome activation that is dependent on caspase-1, and that this process is driving fibrosis. Furthermore, we found that the pathogenic cell that drives the increased collagen synthesis in the skin and organs, the myofibroblast, could be phenotypically altered by inhibiting caspase-1. Specifically, we observed that α-smooth muscle actin stress fibres were thinner in diameter and overall contained less protein when caspase-1 signalling was inhibited. Interestingly we observed no change in α-smooth muscle actin expression in quiescent fibroblasts and f-actin expression was unaffected by caspase-1 inactivation [41]. These findings were further recapitulated in NLRP3- and ASC-deficient mice in a model of dermal fibrosis. The induction of dermal fibrosis with subcutaneous injections of bleomycin was inhibited in the knockout mice, as was pulmonary fibrosis. Our findings suggest that active caspase-1 regulates SSc fibrosis and suggests that there may be autocrine signalling mediated by IL-1β and/or IL-18 that promotes the profibrotic phenotype in these patients.

Recently it was found that stimulation of cardiac fibroblasts, but not cardiomyocytes, with conditions mimicking hypoxia and reoxygenation stimulated the inflammasome and that this could lead to fibrosis [83]. Kawaguchi et al [83], found that under these conditions reactive oxygen species and potassium efflux were the driving forces behind inflammasome activation. ASC-deficient mice had attenuated responses to ischaemia–reperfusion and reduced numbers of infiltrating macrophages and neutrophils. This study provides further evidence that fibroblasts may act as sentinel cells capable of sensing danger signals that are a result of ischaemia and reperfusion, causing an enhanced inflammatory response in the heart and inciting the deposition of collagens.

The NLRP3 inflammasome is involved in pancreatic damage that can lead to diabetes [84]. A study was performed utilizing a high-fat diet in C57BL/6 mice. After 6 weeks of the diet, the inflammasome was found to be activated in adipose tissues and the resulting damage to the pancreas was mediated by IL-1β and increased levels of reactive oxygen species. The investigators observed increased pancreatic islet fibrosis and this was found to be dependent on the NLRP3 inflammasome [84].

Manipulating inflammasome signalling to abrogate fibrosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References

Understanding the signalling that is elicited by the NLRP3 inflammasome could be employed to abrogate fibrosis or improve wound healing (Table 1). As stated above, the FDA is yet to approve a drug that is efficacious for the treatment of fibrosis. Therefore, pursuing molecules with the potential to modulate the inflammasome or inflammasome-mediated products may identify effective therapies for the treatment of this difficult group of diseases.

Table 1. Activators of the NLRP3 inflammasome that promote or abrogate fibrosis
Compounds signalling the NLRP3 inflammasome that promote fibrosisAlum [113-115]

Asbestos/Libby amphibole [116]

β-Glucan [117, 118]

Bleomycin [41, 78]

Cholesterol crystals [119, 120]

Hemozoin crystals [121]

Nanoparticles [122, 123]

Ovalbumin [124-126]

Salmonella typhimurium [127, 128]

Serum amyloid A [129]

Statins [132]

Uric acid crystals [18, 80]

Compounds signalling the NLRP3 inflammasome that abrogate fibrosisChlamydia pneumoniae [27]

Influenza A (Thomas, 2009 5696/id)

Streptolysin O/ML-05 [68-70]

Glyburide/glibenclamide [85, 89]

Parthenolide [133]

Colchicine [101-103]

Some inhibitors of the NLRP3 inflammasome have been shown to reduce fibrosis and potentially these therapies could be developed to regulate the deposition of collagens in tissues and promote wound healing (Table 1). It is unlikely that these inhibitors will be effective across the entire spectrum of fibrotic disorders or be effective in all chronic wounds; however, they suggest that modulating this pathway may be a viable therapeutic modality. To date, there is no compound that can stimulate the inflammasome to promote wound healing; however, several compounds have been identified that target the NLRP3 inflammasome or its downstream signalling products that could be utilized as therapeutics for fibrotic diseases:

  • Glyburide (Glibenclamide) has been FDA-approved for the treatment of type 2 diabetes; however, it was recently discovered that the mode of action by this drug is to inhibit the NLRP3 inflammasome by preventing ATP-sensitive potassium channel signalling and inducing membrane depolarization [85]. The depolarization in the membrane causes voltage-dependent calcium channels to open, resulting in an increase in intracellular calcium and potassium. It is this change in intracellular calcium and potassium that inactivates the inflammasome. One of the effects of Glyburide was reduced extracellular matrix formation by mesangial cells in environments containing high glucose. High glucose levels can lead to cell signalling abnormalities in mesangial cells that promote enhanced TGFβ1 expression, leading to the deposition of extracellular matrix in the kidney [86, 87] and in some instances leading to scleroedema diabeticorum in the skin [88]. The effectiveness of Glyburide at inhibiting collagens was more pronounced at lower concentrations of 0.01 μm than at higher concentrations of 1.0 μm [89], and this study highlights that modulating the inflammasome may be a viable therapeutic modality for fibrosis. In a normoglycaemic individual, there would be the propensity for hypoglycaemia if Glyburide were used to treat fibrosis; however, this complication would be less likely to happen if smaller doses of the drug were required.
  • Parthenolide prevents the activation of multiple inflammasomes inhibiting caspase-1 activation and NF-κB signalling [90]. Parthenolide has been FDA-approved for the treatment of cancer and recently it was determined that cancer is an inflammasome-driven disease [91, 92]. A study by Jia and Turek [93] reported that Parthenolide was able to reduce collagen production in 3T3-Swiss mouse fibroblasts.
  • Z-VAD-FMK/Z-YVAD-FMK is a caspase inhibitor that is frequently used to study the role of inflammatory caspases as a result of inflammasome signalling. Recent studies have used this inhibitor as a neuroprotective agent in bacterial meningitis [94, 95]. Z-VAD-FMK (carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone) is a pan caspase inhibitor and is known to inactivate caspase-1, caspase-3, caspase-4, caspase-5 and caspase-8 [96]. Kuwano et al [96] found that Z-VAD-FMK abrogated bleomycin-induced collagen deposition in a murine model of pneumopathy. Artlett et al [41] studied the efficacy of Z-YVAD-FMK in fibroblasts isolated from the fibrotic lesions of patients with systemic sclerosis and found that inhibition of caspase reduced collagen secretion. These studies were further confirmed with caspase-1 siRNA studies demonstrating that caspase-1 activation was promoting fibrosis in this disease [41].
  • Colchicine has been used for the treatment of autoinflammatory diseases [97, 98] and for gout [99], and these diseases are driven by inflammasome signalling. Colchicine does not directly interact with the inflammasome but is believe to block the signalling upstream of the NLRP3 inflammasome. Colchicine was found to interfere with phagocytosis and microtubule formation (reviewed in [100]). Keloid has been successfully treated with colchicine [101], in addition to diabetic scleroedema [102, 103] and scleroderma [104]. A small study investigated the efficacy of colchicine in scleroderma patients and found improvement in skin scores [104]; however, anecdotally, colchicine does not appear to be effective in clinical practice [105]. This could depend several factors: how the inflammasome is activated; what is activating the inflammasome; or whether microtubule signalling is involved in fibrotic lesions in scleroderma. Finally, colchicine has been successfully used to prevent interstitial fibrosis in renal transplant recipients who have familial Mediterranean fever [97] and retroperitoneal fibrosis [106].
  • Anakinra (kineret) and thalidomide (thalomid) do not directly target the NLRP3 inflammasome but inhibit downstream signalling of the inflammasome either by inactivating IL-1 receptor signalling or inhibiting caspase-1 activity [107], respectively. Anakinra has been successfully used in the treatment of rheumatoid arthritis (reviewed in [108]); however, some studies report that it may have an anti-fibrotic effect, successfully inhibiting fibrosis in animal models [78, 109]; however, studies of its efficacy at inhibiting fibrosis in humans are yet to be performed. Thalidomide inhibits fibrosis in animal studies and in fibrosing diseases [110, 111] and the resulting inhibition of caspase-1 by thalidomide was found to decrease TGFβ1 and ERK1/2 signalling [112].


  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References

This review has brought together diverse information regarding the role of the NLRP3 inflammasome in wound healing and fibrosis (Figure 1). In the fibrotic setting, a chronically activated inflammasome mediating the continuous release of IL-1β and IL-18 could conceivably maintain the profibrotic phenotype, whereas the transient release of IL-1β and IL-18 may limit the expression of collagen. Whether fibrosis requires the activation of a single inflammasome (the NLRP3 inflammasome) or requires co-stimulatory signals driven by other inflammasomes is yet to be determined. Inhibition of the NLRP3 inflammasome may prevent fibrosis. Alternatively, specifically stimulating the inflammasome may prove to be effective in promoting wound healing. Thus, not only has understanding the roles of the inflammasome in chronic inflammatory diseases mediated by pathogens proved informative but, with further research, understanding the roles of inflammasomes in diseases that promote collagen synthesis or impair wound healing will identify novel therapies for this spectrum of diseases that, to date, have been difficult to treat.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Wound healing and fibrosis
  5. The inflammasomes
  6. Wound healing
  7. Fibrosis
  8. Manipulating inflammasome signalling to abrogate fibrosis
  9. Summary
  10. References
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