Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis

Abstract

Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment.

Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages

“…One possibility is that enzymes, such as metalloproteinases and/or cathepsins, secreted during inflammation or released by cells undergoing cytolysis/necrosis may be responsible for the cleavage of pro-IL-1β in the extracellular milieu as described in other experimental models ( 75 – 77 ). Interestingly, in an animal model of viral myocarditis mice deficient in CTSB showed improved survival, reduced inflammatory cell tissue infiltration, and reduced IL-1β production, suggesting the CTSB aggravates the disease through activating the inflammasome-dependent IL-1β production and promoting pyroptosis ( 78 ).…”

Lysosomal membrane permeabilization and cell death

“…These proteins trigger the prion‐like assembly of the inflammasome adaptor ASC into a pyroptosome, a filamentous helical structure that recruits caspase‐1, leading to the maturation of IL‐1β‐family cytokines and gasdermin‐D, and consequent release of cytokines into the extracellular space . Cholesterol crystals, protein aggregates such as β‐amyloid, and bacterial products disrupt lysosomal integrity and activate the NRLP3 inflammasome, inducing cytokine release and cell death . Interestingly, in most of these settings, cathepsin inhibition by genetic or pharmacological means blocks inflammasome activation and cell death .…”

“…Cholesterol crystals, protein aggregates such as β‐amyloid, and bacterial products disrupt lysosomal integrity and activate the NRLP3 inflammasome, inducing cytokine release and cell death . Interestingly, in most of these settings, cathepsin inhibition by genetic or pharmacological means blocks inflammasome activation and cell death . Recent data also show that ASC specks can be released outside the cell during inflammasome‐mediated cell death.…”

Morroniside alleviates coxsackievirus B3-induced myocardial damage apoptosis via restraining NLRP3 inflammasome activation

“…35 CVB3, as has been demonstrated by many epidemiological studies, is the most common pathogen for viral myocarditis. 33,36 Although the regulatory mechanisms underlying CVB3-induced dilated cardiomyopathy are still poorly dened, accumulating evidences suggest that the main pathologic factor of viral myocarditis is overwhelming inammation. 36 Importantly, it has been demonstrated that NLRP3 inammasome activation induced by CVB3 infection is a central player in developing myocardial dysfunction.…”

“…33,36 Although the regulatory mechanisms underlying CVB3-induced dilated cardiomyopathy are still poorly dened, accumulating evidences suggest that the main pathologic factor of viral myocarditis is overwhelming inammation. 36 Importantly, it has been demonstrated that NLRP3 inammasome activation induced by CVB3 infection is a central player in developing myocardial dysfunction. 37 In this case, inhibition of NLRP3 inammasome activation is suggested as the most promising strategy for alleviating CVB3-induced myocardial damage.…”