Abstract
Mycobacterium tuberculosis (Mtb) remains a significant threat to global health as it induces granuloma and systemic inflammatory responses during active tuberculosis. Mtb can induce macrophage pyroptosis, leading to the release of IL-1β and tissue damage, promoting its spread. Here, we established an in vitro Mtb-infected macrophage model to seek an effective antipyroptosis agent. Baicalin, isolated from Radix Scutellariae, was found to reduce pyroptosis in Mtb-infected macrophages. Baicalin could inhibit activation of the PERK/eIF2α pathway and thus downregulates TXNIP expression and subsequently reduces activation of the NLRP3 inflammasome, resulting in reduced pyroptosis in Mtb-infected macrophages. In conclusion, baicalin reduced pyroptosis by inhibiting the PERK/TXNIP/NLRP3 axis and might thus be a new adjuvant host-directed therapy (HDT) drug.
Highlights
As one of the top 10 causes of death worldwide and the leading cause of death caused by a single infectious agent, tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb)
Pyroptosis is a form of programmed cell death characterized by upregulated expression of caspase-1cleaved gasdermin D (GSDMD), which forms membrane pores and promotes the release of proinflammatory mediators, including IL-1β, in response to the adverse effects of certain bacteria [11]
The results revealed that Mtb infection could increase the release of Lactate Dehydrogenase (LDH) at different time points, whereas treatment with baicalin can reverse this effect within 48 h and 72 h in RAW264.7 cells and primary peritoneal macrophages (Figures 1(c) and 1(d))
Summary
As one of the top 10 causes of death worldwide and the leading cause of death caused by a single infectious agent, tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb). Mtb can induce excessive inflammatory responses by infecting macrophages in the host, exacerbating tissue damage and patient symptoms [1]. Host-directed therapy (HDT) is an emerging treatment concept that utilizes drugs to enhance protective immune responses against the pathogen or reduce exacerbated inflammatory responses, to balance immune reactivity and protect the host [3]. Since the excessive inflammatory response of macrophages induced by Mtb infection is the key factor in the pathological damage to a TB patient, the most important measure to alleviate the symptoms of patients is suppressing the excessive inflammatory response when the bacteria cannot be cleared in time [4]. Finding drugs based on HDT might help the host immunity system “correctly” respond to Mtb infection and indirectly enhance the effectiveness of anti-TB drugs
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