The inflammasome in biomaterial‐driven immunomodulation
2022; Wiley; Volume: 16; Issue: 12 Linguagem: Inglês
10.1002/term.3361
ISSN1932-7005
AutoresDaniela P. Vasconcelos, Artur P. Águas, Judite N. Barbosa,
Tópico(s)Immune cells in cancer
ResumoJournal of Tissue Engineering and Regenerative MedicineVolume 16, Issue 12 p. 1109-1120 REVIEW ARTICLEOpen Access The inflammasome in biomaterial-driven immunomodulation Daniela P. Vasconcelos, Daniela P. Vasconcelos i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal INEB - Instituto de Engenharia Biomédica, Porto, PortugalSearch for more papers by this authorArtur P. Águas, Artur P. Águas ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal UMIB - Unit for Multidisciplinary Biomedical Research of ICBAS - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, PortugalSearch for more papers by this authorJudite N. Barbosa, Corresponding Author Judite N. Barbosa judite@ineb.up.pt orcid.org/0000-0003-1852-2790 i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal INEB - Instituto de Engenharia Biomédica, Porto, Portugal ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal Correspondence Judite N. Barbosa, i3S - Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal. Email: judite@ineb.up.ptSearch for more papers by this author Daniela P. Vasconcelos, Daniela P. Vasconcelos i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal INEB - Instituto de Engenharia Biomédica, Porto, PortugalSearch for more papers by this authorArtur P. Águas, Artur P. Águas ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal UMIB - Unit for Multidisciplinary Biomedical Research of ICBAS - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, PortugalSearch for more papers by this authorJudite N. Barbosa, Corresponding Author Judite N. Barbosa judite@ineb.up.pt orcid.org/0000-0003-1852-2790 i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal INEB - Instituto de Engenharia Biomédica, Porto, Portugal ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal Correspondence Judite N. Barbosa, i3S - Instituto de Investigação e Inovação em Saúde, Rua Alfredo Allen, 208, 4200-125 Porto, Portugal. Email: judite@ineb.up.ptSearch for more papers by this author First published: 03 November 2022 https://doi.org/10.1002/term.3361AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Inflammasomes are intracellular structures formed upon the assembly of several proteins that have a considerable size and are very important in innate immune responses being key players in host defense. They are assembled after the perception of pathogens or danger signals. The activation of the inflammasome pathway induces the production of high levels of the pro-inflammatory cytokines Interleukin (IL)-1β and IL-18 through the caspase activation. The procedure for the implantation of a biomaterial causes tissue injury, and the injured cells will secrete danger signals recognized by the inflammasome. There is growing evidence that the inflammasome participates in a number of inflammatory processes, including pathogen clearance, chronic inflammation and tissue repair. Therefore, the control of the inflammasome activity is a promising target in the development of capable approaches to be applied in regenerative medicine. In this review, we revisit current knowledge of the inflammasome in the inflammatory response to biomaterials and point to the yet underexplored potential of the inflammasome in the context of immunomodulation. 1 THE INFLAMMASOME In 2002 the research group of Jurg Tschopp, from the University of Lausanne, Switzerland, presented the concept of inflammasome for the first time. They found that the activation of the pro-inflammatory protease, caspase-1, requires a large molecular platform and named it the inflammasome (Martinon et al., 2002). The exciting report of this multiprotein complex that has the ability of sensing danger and thus initiate an inflammatory response led to a revival of the research on innate immunity (Dagenais et al., 2012). It is now accepted that the stimulation of the innate immunity is not only due to the recognition of pathogen-associated molecular patterns (PAMPs). It also requires the presence of danger-associated molecular patterns (DAMPs) that are secreted by injured cells, and also, of lifestyle-associated molecular patterns (LAMPs) that are the immunostimulatory molecular patterns in sterile inflammation associated, for example, with bioengineered implantable devices (Matzinger, 1994; Zindel & Kubes, 2020). Pattern-recognition receptors recognize PAMPs, DAMPs and LAMPs, being the most studied the toll-like receptors (TLRs). Activated TLRs will induce different signaling cascades resulting for instance in the production of inflammatory cytokines (Martinon et al., 2009). Inflammasomes can therefore be viewed as large cytoplasmic protein complexes (Figure 1) that have the ability of recognizing PAMPs, DAMPs and LAMPs. The inflammasome contains a nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR), the adaptor molecule apoptosis-associated speck like protein containing a card (ASC) and caspase-1. The NLRs have the important function of surveying the intracellular microenvironment for the presence of metabolic perturbations, toxic substances and infection. When NLRs sense danger signals they undergo oligomerization and form macromolecules that have the ability of activating different inflammatory pathways (Zhong et al., 2013). The assembly of the NLRs, ASC and caspase-1 induces the formation of a penta- or heptamer structure: the inflammassome (Strowig et al., 2012). The assembly of the inflammasome causes the activation of inflammatory caspases that will lead to the cleavage of pro-interleukin (IL)-1β and pro-IL-18 into IL-1β and IL-18, and also a type of cell death, pyroptosis (Lamkanfi & Dixit, 2014). FIGURE 1Open in figure viewerPowerPoint NLRP 3 Inflammasome activation. (1) Priming and activation stimuli induce NLRP3 oligomerization that recruits procaspase-1 through apoptosis-associated speck like protein containing a card (ASC). The inflammasome complex also recruits NIMA-related kinase 7 (NEK7) that mediates interactions between adjacent NLRP3 subunits. (2) Within the inflammasome, procaspase-1 undergoes autocatalytic processing, resulting in active caspase-1. NLRP3, Nucleotide-binding and oligomerization domain (NOD)-, Leucine-rich repeats (LRR) and pyrin domain-containing protein 3 (PYD); NATCH, nucleotide-binding domain; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD): NEK7, NIMA-related kinase 7. Different NLRs, upon activation, form inflammasomes as for example, NLRP1, NLRP3, NLRC4, NLRC5 and NAIP2 (Jha et al., 2017). The NLR protein 3 inflammasome (NLRP3 inflammasome), also recognized as cryopyrin or NALP3, is currently the better described inflammasome, being present predominantly in myeloid cells. The NRLP3 inflammasome is activated in response to stimulation by PAMPs, DAMPs and/or LAMPs of macrophages that will secrete extensive amounts of IL-1β and IL-18 through caspase-1 activation (Latz, 2010; Ogura et al., 2006). The process of NLRP3 inflammasome assembly is not completely appreciated, but it is known that it is tightly regulated and its activation requires two-step signals—first, it must be primed, and then activated (Figure 2) (Lamkanfi & Dixit, 2014). The first activation signal will cause de enhancement of the expression of the inflammasome constituents and will target proteins through the activation of the nuclear factor kappa light chain enhancer of activated B cells (Bauernfeind et al., 2009). The second activation signal will promote the oligomerization of the different components of the inflammasome, leading pro-caspase-1 to an autocatalytic processing causing caspase-1 activation that will in turn cleave pro-IL-1β and pro-IL-18 into the mature and active forms. Caspase-1 will also cleave gasdermin D that inserts its N-terminal domain (GSDMDNterm) into cellular membranes, permeabilizing the membrane to the release of the mature cytokines and to pyroptotic cell death (Evavold et al., 2018; Sborgi et al., 2016). The second NLRP3 activating signal comprises three main mechanisms: (i) formation of reactive oxygen species; (ii) lysosomal damage; and (iii) intracellular potassium efflux (Hafner-Bratkovic & Pelegrin, 2018; Lima et al., 2013; Petrilli et al., 2007). NIMA-related kinase 7 (NEK7), a serine-threonine kinase, was recently considered to be crucial for NLRP3 inflammasome activation. Upon inflammasome activation, the NEK7-NLRP3 synergy rises, and NEK7 oligomerizes with NLRP3 into a complex that is essential for ASC speck formation and caspase 1 activation. Thus, NEK7 seems to be an important component, in particular to the NLRP3 inflammasome (Schmid-Burgk et al., 2016). Though most Pattern-recognition receptors have limited specificity for one or few related PAMPs, DAMPs or LAMPs, NLRP3 is exclusive since it is triggered by a wide diversity of unrelated stimuli. NLRP3 is triggered both in pathogen infections and in sterile inflammation. Several different endogenous molecules that are indicative of injury or danger will stimulate the NLRP3 inflammasome, meaning that the NLRP3 inflammasome is able to detect sterile danger signals. These signals include extracellular adenosine triphosphate (ATP), uric acid and hyaluronan that are released by injured cells (Schroder & Tschopp, 2010). The expression of NLRP3 was detected in different cell types such as granulocytes, monocytes, macrophages, B and T lymphocytes, dendritic cells, osteoblasts and epithelial cells, suggesting an important role in the immune response against different threats. Therefore, the majority of studies on NLRP3 inflammasome have been performed in cells of the immune system (Lamkanfi & Kanneganti, 2010). FIGURE 2Open in figure viewerPowerPoint NLRP3 inflammasome activators and inhibitors. The signal 1 (priming; left) is provided by the activation of cytokines or pathogen-associated molecular patterns (PAMPs), leading to the transcriptional upregulation of NLRP3 (Nucleotide-binding and oligomerization domain (NOD)-, Leucine-rich repeats (LRR)—and pyrin domain-containing protein 3 (PYD)) inflammasome components. Signal 2 (activation; right) is provided by numerous PAMPs, danger-associated molecular patterns (DAMPs) (particulates, crystals, adenosine triphosphate (ATP)) and lifestyle-associated molecular patterns (LAMPs) (Bioengineering implantable devices, cholesterol crystals) that activate multiple upstream signaling events. These include K+ efflux, Ca2+ flux, lysosomal disruption, reactive oxygen species (ROS) production. Oligomerization of the inflammasome activates caspase1, which in turn cleaves pro-IL-1b and pro-IL-18. Gasdermin D (GSDMD) is also cleaved and inserts its N-terminal domain (GSDMDNterm) into cellular membranes, forming pores to the release of the mature cytokines and inducing pyroptosis. ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; ATP, adenosine triphosphate; CNS, central nervous system; DAMPs, danger associated molecular patterns; IL-, interleukin; LAMPs, lifestyle associated molecular patterns; LRR, leucine-rich repeat; MSU, monosodium urate; NACHT, central nucleotide-binding and oligomerization; NEK7, NIMA-related kinase 7; NF-k, nuclear factor-kB; P2X7, P2X purinoceptor 7; PAMPs, pathogen associated molecular patterns; PYD, pyrin domain; ROS, reactive oxygen species; TLR, Toll-like receptor. 2 INFLAMMASOME DISORDERS AND ITS IMPLICATIONS IN HUMAN DISEASES Inflammation is a protective response to a noxious stimulus. A defective inflammation leads to continuous infection, and excessive inflammation can originate disease. The inflammasome is one of the most relevant mediators in these processes (Davis et al., 2011). Consequently, inflammasome activity is highly controlled to avoid excessive cytokine production or cell death, being regulated at two levels, transcriptional (upregulation of inflammasomes components NLRP3, caspase 1 and pro-IL-1β) and post-transcriptional (ubiquitylation, phosphorylation and sumoylation) (Yang et al., 2019). The expression of inflammasome sensors in resting cells is rather low and insufficient to be induced. Inflammasome alterations have been associated to autoinflammatory, autoimmune and neurodegenerative diseases (multiple sclerosis, Alzheimer's disease (AD), Parkinson's disease), metabolic disorders (atherosclerosis, type 2 diabetes and obesity) and cancer, playing contributing roles in the beginning and development of those pathologies (Figure 3) (Strowig et al., 2012). FIGURE 3Open in figure viewerPowerPoint NLRP3 inflammasome role in disease. NLRP3 inflammasome has a key function in tissue repair and in host response not only to bacteria, fungi, viruses, and possible parasites, but also to danger-associated molecular patterns (DAMPs) and lifestyle-associated molecular patterns (LAMPs). Anomalous or exacerbated NLRP3 inflammasome activation is linked with the development of many diseases, such as, Alzheimer's Disease (AD), autoinflammatory diseases and cancer. The role of NLRP3 inflammasome in cancer is controversial, since there are evidences of a protective anti-tumorigenic effect as well as a pro-tumorigenic role depending of the cancer type. The correlation of NLRP3 inflammasome with a plethora of diseases hints a substantial interest in the scientific community to determine the effective NLRP3 inflammasome inhibitor For instances, in AD is described an accumulation of amyloid-β (Aβ) in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, leading to neurodegeneration (Ising & Heneka, 2018), the NLRP3 inflammasome has been related to the advance of Aβ pathology in AD models in mice. Furthermore, Venegas et al. (2017) showed that Aβ deposition is followed by innate immune system activation involving the formation of ASC specks in microglia in an inflammasome-dependent manner. The use of an anti-ASC antibody impaired the increase in Aβ pathology in an experimental model of AD. In addition, Yin et al. (2018) observed an increase of NLRP3 inflammasome in TgCRND8 mice, a mouse model of AD, inhibited by the treatment with JC-124, a small molecule that harm NLRP3 oligomerization. More recently, Ising et al. (2019) demonstrated a decrease of NLRP3 inflammasome activity reduced tau hyperphosphorylation and aggregation in AD. The link between inflammasome activity and the pathophysiology of Aβ-plaque and tau hyperphosphorylation suggests that the targeting of inflammasomes could represent a novel treatment for AD. NLRP3 mutations have been linked with a rare hereditary autoinflammatory diseases known as cryopyrin-associated periodic syndrome (CAPS). Cryopyrin-associated periodic syndrome comprise three phenotypes: familial cold auto-inflammatory syndrome, Musckle-Wells syndrome, and chronic infantile neurological, cutaneous, and articular syndrome all of them, characterized by systemic inflammation (Hoffman & Wanderer, 2010). Local manifestations disturb multiple tissues such as skin, joints, muscles, eyes and the central nervous system. Cryopyrin-associated periodic syndrome results from a gain-of-function mutation of the NLRP3 gene, leading to overproduction of IL-1 (Dinarello, 2009). The rarity of CAPS and the similarity of symptoms with other diseases delay their accurate diagnosis. IL-1 inhibitory agents, anakinra (a modified IL-1RA that binds and antagonized the IL-1 receptor), canakinumab (an IL-1 neutralizing antibody) and rilonacept (ligand-binding domains of the extracellular portions of IL-1 receptor component) are the main therapeutic approach for CAPS. The blocking of IL-1 leads to a rapid and continual reversal of daily symptoms, diminishing long-term disease consequences (Hoffman, 2009; Lachmann et al., 2009; Sibley et al., 2012). The early diagnosis and treatment for CAPS patients are key to prevent organ damage. Inflammation and immunosuppression are fundamental for cancer cells survival and progression. The role of NLRP3 inflammasome in cancer is arguable, since there are suggestions of a protective anti-tumorigenic role but also a pro-tumorigenic effect, depending of the cancer type (Hamarsheh & Zeiser, 2020; Kantono & Guo, 2017; Karki & Kanneganti, 2019). Kaplanov et al. (2019) demonstrated that IL-1β in a 4T1 experimental mouse model of triple-negative breast cancer has an immunosuppressive, pro-tumorigenic role. Treatment with anti-IL-1β antibodies followed by anti-PD-1 antibodies fully abolished tumor development. Chronic inflammation of mucosal surfaces and tissue injury observed in inflammatory bowel disease favor colorectal cancer. Huber et al. (2012) found that NLRP3 inflammasome detects tissue damage and promotes IL-18 production that inhibits IL-22 binding protein, leading to IL-22 secretion and tumor growth. A possible explanation for these observations could be the fact that similar mediators and pathways in wound healing also have the ability to support tumorigenesis. On the other hand, some authors demonstrated that NLRP3 inflammasome could also have an anti-tumorigenic role: In divergence with the role of NLRP3 inflammasome in colorectal cancer cited above, Dupaul-Chicoine et al. (2015) stated that IL-18 release through NLRP3 pathway restrains colorectal cancer metastatic growth in liver by the increase of natural killer cell tumoricidal activity. The knowledge of the interaction between immunity and inflammation, inflammasomes, and cancer type may be crucial for the development of new therapies for cancer prevention and treatment. The strong participation of the NLRP3 in inflammation and its roles in different kind of diseases makes it an attractive drug target (Figure 2). Current clinical approved treatment of NLRP3- related pathologies aims the inflammasome-derived cytokine IL-1β with IL-1β antibodies or recombinant IL-1β receptor antagonist: canakinumab and anakinra (Yang et al., 2019). However, they have disadvantages since inflammasome activation is important for host defense against a plethora of pathogens, and hence loss of IL-1β can have deleterious effects on immune defense. Over the last years, some blockers of NLRP3 inflammasome pathway have been developed, few of which have been validate in animal models. MCC950 is a compound that specifically inhibits NLRP3 inflammasome activation, but its molecular mechanism has not been fully elucidated (Coll et al., 2015). Cy-09 and OLT1177 can inhibit the ATPase activity of the NACHT domain, which is critical for NLRP3 oligomerization (Jiang et al., 2017; Kuwar et al., 2019). JC-124 blocks the expression of NLRP3, ASC, Caspase 1 and pro-IL-1b, but its molecular mechanism are still under investigation (Marchetti et al., 2015). Due the number of individuals with serious conditions driven by NLRP3, there is a strong motivation for the discovery and clinical development of molecules that selectively antagonize NLRP3. Although these inhibitors have shown therapeutic potential, the food and drug administration and other regulatory agents did not approve any of them. In addition, the NLRP3 structure and activation mechanisms are still poorly understood which has delayed the development of novel therapeutics. Nevertheless, there are pre-clinical evidences that the pharmacological inhibition of the NLRP3 inflammasome pathway has for example, a neuroprotective role in different disease models, therefore providing convincing arguments to further evaluate the potential of targeting the NLRP3 inflammasome (Jose et al., 2022). 3 THE ACTIVATION OF THE INFLAMMASOME BY BIOMATERIALS Tissue engineering and regenerative medicine are focused in the development of therapies to regenerate or replace injured, diseased, or defective cells, tissues, or organs to restore or establish function and structure (Daar & Greenwood, 2007). Many of the developed approaches are biomaterial-based which makes the understanding of innate and adaptive immune responses critical for the success of their application (Sefton et al., 2008). Great advances in this area have been achieved by James Anderson that has presented us a pathologist perspective on the foreign body reaction (FBR) to biomaterials (Table 1) in several manuscripts that are still today a reference for researchers in this field (Anderson, 1988, 2001; Anderson et al., 2008). More recently, Franz et al. (2011) presented a thorough review on the immune responses to biomaterials and were one of the first authors to address the importance of developing biomaterials capable of modulating the immune response and to present the concept of immunomodulatory biomaterials, however the concept of inflammasome activation by biomaterials was not herein explored. A few years latter Christo et al. (2015) present a detailed review on innate immunity and biomaterials and discuss the role of the inflammasome in the inflammatory response to biomaterials. TABLE 1. The foreign body reaction (FBR) to biomaterials (Anderson, 2001; Anderson et al., 2008; Christo et al., 2015; Franz et al., 2011) Phases of the foreign body reaction Brief description Timescale Biomaterial implantation The implantation of a biomaterial or biomedical device causes injury in tissues or organs leading to the onset of an inflammatory response. t = 0 Protein Adsorption Blood proteins will adsorb to the surface of the biomaterial leading to the activation of the coagulation and complement system and to the activation of platelets. t > 1 s Inflammatory cells recruitment Inflammatory cells, initially predominantly polymorphonuclear leukocytes (PMNs) are recruited to the implant site. Activated PMNs secrete chemokines that act as chemoattractants to monocytes, macrophages, immature dendritic cells and lymphocytes. t = 60 min Cell adhesion to the biomaterial Monocytes differentiate into macrophages that will adhere to the surface of the biomaterial and secrete reactive species in an attempt to degrade and phagocyte the material. In larger materials, macrophages fuse and form foreign body giant cells (FBGCs). t = 1–15 days Fibrous Capsule formation Macrophages and FBGCs release factors such as transforming growth factor beta (TGF-b) and platelet-derived growth factor (PDGF) that recruits and activates fibroblasts and endothelial cells. Activated fibroblasts will synthesize collagen leading to the formation of a fibrous capsule and consequently biomaterial encapsulation. t = 3–4 weeks The process of implantation of a biomaterial causes injury to tissues that will release DAMPs and may lead to the activation of the inflammasome pathway. Tissue resident macrophages will be one of the first immune cells to respond to injury. When activated by DAMPs, these tissue resident macrophages will release chemokines and cytokines that will prime the recruitment of polimorphonuclear leukocytes and monocytes to the injured site further activating the inflammatory response (Raziyeva et al., 2021). In Table 2 we summarize some general concepts of the inflammatory response related to the host response to biomaterials. TABLE 2. General concepts of an inflammatory response related to the host response to biomaterials (Coll et al., 2015; Elmore, 2007; Land, 2020; Williams, 2017; Zotova et al., 2016) General concepts of an inflammatory response Acute inflammation Initial phase of the inflammatory response of relatively short duration (minutes to days). Mainly characterized by the exudation of plasma proteins and fluid and by the emigration of leukocytes, mainly polymorphonuclear leukocytes (PMNs), from blood vessels to the injured site. Chronic inflammation Occurs when the inflammatory stimuli persists. Monocytes are recruited to the inflammatory environment and differentiate into macrophages. Macrophages become the predominant inflammatory cell. The constant release of inflammatory mediators leads to permanent activation of macrophages, and the production of chemokines leads to the recruitment of additional inflammatory cells. Systemic inflammation Generalized inflammatory response throughout the whole body. Characterized by the inflammatory reactivity of endotheliocytes, plasma and blood cell factors. Sterile inflammation Sterile inflammation is an inflammatory response that occurs in the absence of microorganisms. Is associated with the recognition of molecules released from injured cells (DAMPs: Damage-associated molecular patterns). Biomaterials induce sterile inflammation. PAMPs Pathogen-associated molecular patterns: Molecular structures produced by microorganisms that are recognized as foreign by the innate immune system. DAMPs Damage-associated molecular patterns: Molecules released upon non-physiological cell death, damage, or stress that are indicative of danger and are sensed by the innate immune system and activate immune cells. There are also exogenous DAMPs such as airborne particles. PRRs Pattern recognition receptors: Expressed on leukocytes interact with PAMPs and DAMPs leading to leukocyte activation. There are different families of PRRs such as toll-like receptors (TLRs) and NOD-like receptors (NLRs). Apoptosis Apoptosis is a process of programmed cell death. This process occurs normally during development and aging but it has also an important role in immune responses. Pyroptosis Pyroptosis is an inflammatory type of programmed cell death that is typically elicited by the inflammasome. It is characterized by the permeation of the plasma membrane leading to the subsequent release of intracellular contents. Inflammasome stimulation by biomaterials is being investigated mainly with bioengineered nanomaterials (Christo et al., 2016; Silva et al., 2017). It has been reported as a component of the inflammatory response to several biomaterials such as gold nanoshells (Nguyen et al., 2012), silver nanoparticles (Yang et al., 2012) and chitin/chitosan (Bueter et al., 2011) but these studies are based mainly in the assessment of the production of IL-1β. There are however more detailed studies available in the literature that address the biological effects of different biomaterials, mainly nanomaterials, on immune cells and on the NLRP3 inflammasome activation that we summarize in the following paragraphs and review on Table 3. On the following section of this manuscript we explore some applications on the targeting of the inflammasome pathway in the context of tissue engineering and regenerative medicine. TABLE 3. Examples of the effect of biomaterials in the inflammasome pathway activation Biomaterial Inflammasome Response Reference Nano-scale based biomaterials Carbon nanoparticles Activation of caspase-1 increased IL-1β production Reisetter et al. (Reisetter et al., 2011) Amino-functionalized polystyrene nanoparticles Assembly of the NLRP3 inflammassome increased IL-1β production Lunov et al. (Lunov et al., 2011) Carboxyl- functionalized or non-functionalized polystyrene nanoparticles No effect on the inflammmasome pathways was observed Silica nanoparticles Increased levels of IL-1β through inflammasome pathway activation Gómes et al. (Gomez et al., 2017) Titanium dioxide nanoparticles Increased gene expression of NLRP3, caspase-1 and IL-1β Abbasi-Oshaghi et al. (Abbasi-Oshaghi et al., 2019) Chitosan-aluminum nanoparticles Activation of the NLRP3 inflammassome increased IL-1β production Lebre et al. (Lebre et al., 2018) Micro-scale based biomaterials Cobalt-Chromium-Molybdenum alloy microparticles Irregular and larger microparticles induced higher levels of IL-1β through inflammasome pathway activation. Caicedo et al. (Caicedo et al., 2013) Hydroxyapatite microparticles Smaller and needle-shaped microparticles lead to activation of the NLRP3 inflammassome increased IL-1β production Lebre et al. (Lebre et al., 2017) Microspheres of poly(methyl methacrylate) Activation of caspase-1 further secretion of IL-1β Malik et al. (Malik et al., 2011) Large-scale based biomaterials Collagen 3D scaffolds Induced assembly of the NLRP3 inflammasome increased IL-1β secretion Court et al. (Court et al., 2019) 3D chitosan scaffolds Impaired NLRP3 inflammasome assembly Vasconcelos et al. (Vasconcelos et al., 2019) Based on the available literature it can be concluded that there is a clear tendency for the activation of the inflammasome pathway by nano- and micro-particles. Reisetter et al. (2011) have performed in vitro studies with macrophages exposed to carbon black nanoparticles that triggered inflammasome activation evaluated by the activation of caspase-1 and ensuing IL-1β production. Lunov et al. (2011) have demonstrated in vitro that amino-functionalized polystyrene nanoparticles caused the assembly of the NLRP3 inflammassome leading to the production of IL-1β. However, this activation was not observed for carboxyl- or non-functionalized particles. Gomez et al. (2017) described that silica nanoparticles induced the release of pro-inflammatory cytokines with the involvement of NLRP3 inflammasome constituints. Caicedo et al. (2013) investigated the importa
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