OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection

Abstract

Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections.

Classifying Integrated Signature Molecules in Macrophages of Rheumatoid Arthritis, Osteoarthritis, and Periodontal Disease: An Omics-Based Study

“…It is involved in the stress response pathway, actively regulating the p38 MAP kinase pathway and TCR signaling in naive CD4+ T cells. It is well-known for its role in inflammatory diseases, macrophage activation, and bacterial growth [ 97 , 98 ]. According to research, STK39 dysregulation affects MMP2 (matrix metallopeptidase 2) and MMP9 (matrix metallopeptidase 9), thus actively participating in osteosarcoma [ 99 ].…”

Diving into drug-screening: zebrafish embryos as an in vivo platform for antimicrobial drug discovery and assessment

“…The study by Hortel et al ( 2022 ) employed zebrafish embryos infected with M. marinum and in vitro THP-1 macrophage– M. tuberculosis systems to investigate the role of the WNK-OSXR1 signaling pathway in infection-induced inflammasome activation. The research demonstrated that pathogenic mycobacteria, particularly M. marinum , elevate macrophage K+ concentration and induce the expression of OXSR1.…”

One Host-Multiple Applications: Zebrafish (Danio rerio) as Promising Model for Studying Human Cancers and Pathogenic Diseases

“…The aim of testing cancers is very often to discover the function of genes. In this case, the commonly used method is (again) CRISPR, which enables editing of the genome and alters gene transcription [ 98 ]. For investigation of gene function, the most common methods are based on immunochemistry [ 99 ] or genes expression analysis by qPCR [ 98 ].…”

“…In this case, the commonly used method is (again) CRISPR, which enables editing of the genome and alters gene transcription [ 98 ]. For investigation of gene function, the most common methods are based on immunochemistry [ 99 ] or genes expression analysis by qPCR [ 98 ]. In cancer cells, such as any other, every event is promoted by a number of genes involved in many different signaling pathways.…”

“…In contrast, C. auris infection did not lead to NETs formation [ 89 ]. Gene expression analysis of the two kinases involved in the WNK signaling pathway (SPAK and OXSR1) revealed their upregulation during Mycobacterium marinum infection [ 98 ]. The mutation of OXSR1 decreased bacterial burden and intracellular potassium levels.…”