Involvement of cathepsin B in the processing and secretion of interleukin‐1β in chromogranin A‐stimulated microglia

Terada, Kazumasa; Yamada, Jun; Hayashi, Yoshinori; Wu, Zhou; Uchiyama, Yasuo; Peters, Christoph; Nakanishi, Hiroshi

doi:10.1002/glia.20906

Cited by 95 publications

(80 citation statements)

References 37 publications

(43 reference statements)

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“…Rather, the results agree well with previous reports that show that cathepsin B is associated with maturation of IL-1b in the endolysosomal compartment (51) and that stimulation of P2X 7 R induces secretion of cathepsin B (50,52).…”

Section: Saa-induced Inflammasome Activation Is Dependent On Cathepsin Bsupporting

confidence: 93%

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Niemi

Teirilä

Lappalainen

et al. 2011

The Journal of Immunology

249

225

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Serum amyloid A (SAA) is an acute-phase protein, the serum levels of which can increase up to 1000-fold during inflammation. SAA has a pathogenic role in amyloid A-type amyloidosis, and increased serum levels of SAA correlate with the risk for cardiovascular diseases. IL-1β is a key proinflammatory cytokine, and its secretion is strictly controlled by the inflammasomes. We studied the role of SAA in the regulation of IL-1β production and activation of the inflammasome cascade in human and mouse macrophages, as well as in THP-1 cells. SAA could provide a signal for the induction of pro–IL-1β expression and for inflammasome activation, resulting in secretion of mature IL-1β. Blocking TLR2 and TLR4 attenuated SAA-induced expression of IL1B, whereas inhibition of caspase-1 and the ATP receptor P2X7 abrogated the release of mature IL-1β. NLRP3 inflammasome consists of the NLRP3 receptor and the adaptor protein apoptosis-associated speck-like protein containing CARD (a caspase-recruitment domain) (ASC). SAA-mediated IL-1β secretion was markedly reduced in ASC−/− macrophages, and silencing NLRP3 decreased IL-1β secretion, confirming NLRP3 as the SAA-responsive inflammasome. Inflammasome activation was dependent on cathepsin B activity, but it was not associated with lysosomal destabilization. SAA also induced secretion of cathepsin B and ASC. In conclusion, SAA can induce the expression of pro–IL-1β and activation of the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. Thus, during systemic inflammation, SAA may promote the production of IL-1β in tissues. Furthermore, the SAA-induced secretion of active cathepsin B may lead to extracellular processing of SAA and, thus, potentially to the development of amyloid A amyloidosis.

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Section: Saa-induced Inflammasome Activation Is Dependent On Cathepsin Bsupporting

confidence: 93%

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Niemi

Teirilä

Lappalainen

et al. 2011

The Journal of Immunology

249

225

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“…The c-myc-immortalized mouse microglial cell line, MG6 (KIREN Cell Bank), was maintained in DMEM containing 10% fetal bovine serum (ICN Biomedicals) supplemented with 100 M ␣-mercaptoethanol, 10 g/ml insulin, 100 g/ml streptomycin, and 100 U/ml penicillin (BD Falcon) (Takenouchi et al, 2005;Nakamichi et al, 2006). Primary cultured microglia were isolated from the mixed primary cell cultures from the cerebral cortex of 3-d-old wild-type or CatBϪ/Ϫ mice according to the previously described methods (Sastradipura et al, 1998;Terada et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

“…These results further suggest that CatB is involved in CFA-induced inflammatory pain, but not in the nerve injuryinduced neuropathic pain at the spinal cord level. CatB deficiency reduces the CFA-induced production of IL-1 family members in hyperactivated spinal microglia Although IL-1␤ has been demonstrated to be a key pain-related molecule in both pain models (Samad et al, 2001;Sweitzer et al, 2001;Kawasaki et al, 2008;Ren and Torres, 2009), increasing evidence suggests that there are CatB-dependent and CatBindependent mechanisms responsible for the production of mIL1-␤ by microglia/macrophages Terada et al, 2010). To address the question why CatB plays a pivotal role in the induction of CFA-induced inflammatory pain but not in the nerve injury-induced neuropathic pain, we examined the possibility that CatB deficiency affects the production of mIL-1␤ in spinal microglia following CFA injection, but not after the nerve injury.…”

Section: Catb Deficiency Reduces the Cfainduced Long-lasting Tactile mentioning

confidence: 99%

“…CGA, a neuroactive glycoprotein, is known to be a potent microglial activator (Kingham et al, 1999;Terada et al, 2010) and is significantly elevated in subjects with inflammatory diseases, such as rheumatoid arthritis (Di Comite et al, 2009). ATP and LPA are also known as endogenous microglial activators that are involved in the induction of neuropathic pain (Tsuda et al, 2003;Inoue et al, 2004;Coull et al, 2005;Donnelly-Roberts et al, 2007;Fujita et al, 2008).…”

Section: Catb Deficiency Reduces the Cfainduced Long-lasting Tactile mentioning

confidence: 99%

“…The NLRP3 inflammasome is known to consist of the NLR family member, NLRP3, the adaptor protein, ASC, and the effector protein, pro-caspase-1. However, other studies have suggested that CatB is directly involved in the proteolytic cleavage of pro-caspase-1 and the subsequent processing of pro-IL-1␤ in the endosomal/lysosomal system (Schotte et al, 1998;Hentze et al, 2003;Terada et al, 2010). CatB has been demonstrated to be involved in the production of mIL-1␤, which is a key pain-related molecule (Samad et al, 2001;Sweitzer et al, 2001;Kawasaki et al, 2008;Ren and Torres, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

Sun

Hayashi

et al. 2012

J. Neurosci.

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Interleukin (IL)-1␤ and IL-18 play critical roles in the induction of chronic pain hypersensitivity. Their inactive forms are activated by caspase-1. However, little is known about the mechanism underlying the activation of pro-caspase-1. There is increasing evidence that cathepsin B (CatB), a typical lysosomal cysteine protease, is involved in the pro-caspase-1 activation and the subsequent maturation of IL-1␤ and IL-18. In this context, CatB is considered to be an important molecular target to control chronic pain. However, no information is currently available about the role of CatB in chronic pain hypersensitivity. We herein show that CatB deficiency or the intrathecal administration of CA-074Me, a specific CatB inhibitor, significantly inhibited the induction of complete Freund's adjuvant-induced tactile allodynia in mice without affecting peripheral inflammation. In contrast, CatB deficiency did not affect the nerve injury-induced tactile allodynia. Furthermore, CatB deficiency or CA-074Me treatment significantly inhibited the maturation and secretion of IL-1␤ and IL-18 by cultured microglia following treatment with the neuroactive glycoprotein chromogranin A (CGA), but not with ATP. Moreover, the IL-1␤ expression in spinal microglia and the induction of tactile allodynia following the intrathecal administration of CGA depended on CatB, whereas those induced by the intrathecal administration of ATP or lysophosphatidic acid were CatB independent. These results strongly suggest that CatB is an essential enzyme for the induction of chronic inflammatory pain through its activation of pro-caspase-1, which subsequently induces the maturation and secretion of IL-1␤ and IL-18 by spinal microglia. Therefore, CatB-specific inhibitors may represent a useful new strategy for treating inflammation-associated pain.

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Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor

Clark

Wodarski

Guida

et al. 2010

Glia

126

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Microglia respond rapidly to injury, increasing their synthesis and release of inflammatory mediators, many of which contribute to the maintenance of persistent pain following CNS or PNS injury. We have recently shown that the lysosomal cysteine protease Cathepsin S (CatS) expressed by spinal microglia is vital for the full expression of neuropathic pain. Here we evaluated the mechanisms by which CatS release occurs from primary microglia in culture. Stimulation of microglia with lipopolysaccharide (LPS) or adenosine tri-phosphate (ATP) alone was insufficient to induce release of enzymatically active CatS in extracellular media. However, following priming with LPS, ATP at 1 mM but not 50 μM resulted in significant release of CatS in the media and maturation of CatS protein in cell extracts. The enzymatic activity measured in media at neutral pH was specific for CatS as it was completely prevented by the CatS inhibitor LHVS. ATP-induced release of CatS required potassium efflux and both extracellular calcium influx and mobilization of intracellular calcium. Pharmacological modulation of ATP-induced release of CatS enzymatic activity revealed that this was dependent on activation of the P2X7 receptor and intracellular phospholipase C and phospholipase A(2). In addition, ATP-induced CatS release involved p38 mitogen activated protein kinase (MAPK) phosphorylation, but not ERK and PI3K signalling pathways. Thus, as high concentration of extracellular ATP promotes release of active CatS from microglia via P2X7 receptor activation, we suggest that the inhibition of CatS release is one of the mechanisms responsible for P2X7 antagonist efficacy in neuropathic pain.

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Involvement of cathepsin B in the processing and secretion of interleukin‐1β in chromogranin A‐stimulated microglia

Cited by 95 publications

References 37 publications

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor

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