Th17 cells, CD4(+) T cells that secrete interleukin-17 (IL-17), are pathogenic in autoimmune diseases and their development and expansion is driven by the cytokines IL-6, TGF-beta, IL-21, IL-1, and IL-23. However, there are also innate sources of IL-17. Here, we show that gammadelta T cells express IL-23R and the transcription factor RORgammat and produce IL-17, IL-21, and IL-22 in response to IL-1beta and IL-23, without T cell receptor engagement. IL-17-producing gammadelta T cells were found at high frequency in the brain of mice with experimental autoimmune encephalomyelitis (EAE). gammadelta T cells activated by IL-1beta and IL-23 promoted IL-17 production by CD4(+) T cells and increased susceptibility to EAE, suggesting that gammadelta T cells act in an amplification loop for IL-17 production by Th17 cells. Our findings demonstrate that gammadelta T cells activated by IL-1beta and IL-23 are an important source of innate IL-17 and IL-21 and provide an alternative mechanism whereby IL-1 and IL-23 may mediate autoimmune inflammation.
IL-1β is an important inflammatory mediator of type 2 diabetes (T2D). Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during T2D, trigger the Nlrp3 inflammasome and generate mature interleukin (IL)-1β. A T2D therapy, glyburide, suppresses IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first requires priming, a process that involves glucose metabolism and can be facilitated by minimally oxidized low density lipoprotein. Finally, mice transgenic for human IAPP have increased IL-1β in pancreatic islets, which colocalizes with amyloid and macrophages. Our findings reveal novel mechanisms in the pathogenesis of T2D and treatment of pathology caused by IAPP.
It was recently demonstrated that interleukin (IL)-23–driven IL-17–producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I–deficient (IL-1RI−/−) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI−/− compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RI−/− mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RI−/− mice, and IL-23–induced IL-17 production was substantially enhanced by IL-1α or IL-1β, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor κB, and novel protein kinase C isoforms in IL-1– and IL-23–mediated IL-17 production. Tumor necrosis factor α also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.
Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1 secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1 in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1 was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1 and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1 by antigen-presenting cells in an NLRP3-and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1 in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1 through at least two separate mechanisms: by targeting pro-IL-1 for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.IL-1 is an important proinflammatory cytokine, released at sites of infection or injury, that regulates diverse physiological responses, including cellular recruitment, appetite, sleep, and body temperature (1). IL-1 is first produced as a proform in response to inflammatory stimuli, such as TLR ligands. This inactive precursor is cleaved into the bioactive (p17) molecule by caspase 1, following the activation of an inflammasome (2).Inflammasomes are molecular scaffolds that trigger the activation of caspase 1 and subsequent maturation of IL-1 and IL-18. Typically, inflammasomes are formed from at least one member of the cytosolic innate immune sensor family, the NOD-like receptors (NLRs), including NLRP1, NLRP3, and NLRC4, coupled with the adaptor apoptosis-associated specklike protein containing a caspase recruitment domain (ASC or PYCARD) and caspase 1 (2). The NLRP3 inflammasome is the best characterized to date and is activated by a number of endogenous and exogenous signals.Most studies in vitro employ TLR ligands, particularly LPS, to induce pro-IL-1 formation, but in many cases, this is not enough to stimulate inflammasome activation and secretion of the mature cytokine. Instead, a second signal is commonly required, and this can come from a number of endogenous and exogenous sources, including ATP and particulates, including uric acid crystals, amyloid-, silica, asbestos, synthetic microparticles, and alum (3-8). Extracellular ATP triggers the P2X7 ATP-gated ion channel, leading to K ϩ efflux and induces recruitment of the pannexin-1 membrane pore (9). This may then allow extracellular NLRP3 agonists to enter the cell and activate inflammasome assembly (9). Particulates have been proposed to act through one of two mechanisms. Uptake of particulates by phagocytes may lead to lysosomal damage and release of lysosomal products into the cytosol, which a...
Interleukin-33 (IL-33) is a member of the IL-1 family and is involved in polarization of T cells toward a T helper 2 (Th2) cell phenotype. IL-33 is thought to be activated via caspase-1-dependent proteolysis, similar to the proinflammatory cytokines IL-1 beta and IL-18, but this remains unproven. Here we showed that IL-33 was processed by caspases activated during apoptosis (caspase-3 and -7) but was not a physiological substrate for caspases associated with inflammation (caspase-1, -4, and -5). Furthermore, caspase-dependent processing of IL-33 was not required for ST2 receptor binding or ST2-dependent activation of the NF-kappaB transcription factor. Indeed, caspase-dependent proteolysis of IL-33 dramatically attenuated IL-33 bioactivity in vitro and in vivo. These data suggest that IL-33 does not require proteolysis for activation, but rather, that IL-33 bioactivity is diminished through caspase-dependent proteolysis within apoptotic cells. Thus, caspase-mediated proteolysis acts as a switch to dampen the proinflammatory properties of IL-33.
Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Drusen accumulation is the major pathological hallmark common to both dry and wet AMD. Although activation of the immune system has been implicated in disease progression, the pathways involved are unclear. Here we show that drusen isolated from donor AMD eyes activates the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, causing secretion of interleukin-1β (IL-1β) and IL-18. Drusen component C1Q also activates the NLRP3 inflammasome. Moreover, the oxidative-stress–related protein-modification carboxyethylpyrrole (CEP), a biomarker of AMD, primes the inflammasome. We found cleaved caspase-1 and NLRP3 in activated macrophages in the retinas of mice immunized with CEP-adducted mouse serum albumin, modeling a dry-AMD–like pathology. We show that laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, is exacerbated in Nlrp3−/− but not Il1r1−/− mice, directly implicating IL-18 in the regulation of CNV development. These findings indicate a protective role for NLRP3 and IL-18 in the progression of AMD.
Many currently used and candidate vaccine adjuvants are particulate in nature, but their mechanism of action is not well understood. Here, we show that particulate adjuvants, including biodegradable poly(lactide-co-glycolide) (PLG) and polystyrene microparticles, dramatically enhance secretion of interleukin-1 (IL-1) by dendritic cells (DCs). The ability of particulates to promote IL-1 secretion and caspase 1 activation required particle uptake by DCs and NALP3. Uptake of microparticles induced lysosomal damage, whereas particle-mediated enhancement of IL-1 secretion required phagosomal acidification and the lysosomal cysteine protease cathepsin B, suggesting a role for lysosomal damage in inflammasome activation. Although the presence of a Toll-like receptor (TLR) agonist was required to induce IL-1 production in vitro, injection of the adjuvants in the absence of TLR agonists induced IL-1 production at the injection site, indicating that endogenous factors can synergize with particulates to promote inflammasome activation. The enhancement of antigenspecific antibody production by PLG microparticles was independent of NALP3. However, the ability of PLG microparticles to promote antigen-specific IL-6 production by T cells and the recruitment and activation of a population of CD11b ؉ Gr1 ؊ cells required NALP3. Our data demonstrate that uptake of microparticulate adjuvants by DCs activates the NALP3 inflammasome, and this contributes to their enhancing effects on innate and antigenspecific cellular immunity.Caspase-1 ͉ IL-1 ͉ microparticle
The global burden of mortality and morbidity associated with infectious diseases caused by mucosal pathogens remains unacceptably high. Indeed, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic provides a brutal reminder of the continual threat of novel mucosal infectious challenges, in addition to the threat posed by many widespread mucosal infections for which no or only suboptimal vaccines exist. Now more than ever, there is a clear focus on vaccine requirements for respiratory pathogens but, importantly, new and improved vaccines are also urgently needed for numerous enteric pathogens and other agents such as those causing sexually transmitted diseases (STDs) and oncogenic viruses that gain access through the mucosae.Respiratory pathogens remain a prominent cause of global mortality, with lower respiratory tract infections constituting the fourth leading cause of death worldwide 1 . Lower respiratory tract infections are responsible for approximately 2.4 million deaths per annum, with Streptococcus pneumoniae, respiratory syncytial virus (RSV), Haemophilus influenzae B and influenza virus taking a particularly high toll on the young (<5 years old) and older people 2 . There is currently no approved vaccine for RSV infection, which is particularly prevalent in children and infants [2][3][4] , and although there are licensed vaccines targeting respiratory pathogens such as Mycobacterium tuberculosis, S. pneumoniae, Bordetella pertussis and influenza virus, improved vaccines for these pathogens are required to enhance suboptimal protection, particularly at the site of infection, and to increase coverage (Fig. 1). There are indications that innovative mucosal vaccine approaches offer promise for these infections. For example, live attenuated influenza vaccines given intranasally are now an integral part of influenza vaccination strategies with particular application to children 5,6 , intranasally administered B. pertussis vaccines have entered phase II trials 7,8 (Supplementary Table 1) following successful phase I completion, and preclinical data investigating the intranasal delivery of Bacillus Calmette-Guérin for M. tuberculosis have yielded promising results 9 . The emergence of SARS-CoV-2 has firmly demonstrated how deadly and disruptive respiratory pathogens can be, with approximately 2.6 million deaths attributed to this pathogen at the time of writing 10 and estimates that the SARS-CoV-2 pandemic will continue to stunt global economic growth in 2021, particularly in low-income countries 11 . Although an array of effective SARS-CoV-2 vaccines have been designed and implemented, challenges in mass production and deployment
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