2. Academic Validation
  3. Furamidine enhances IL-23-mediated autophagic response through IL-23R-TYK2-STAT3-dependent regulation of intracellular Ca²⁺ level to facilitate mycobacterial clearance in human macrophages

Furamidine enhances IL-23-mediated autophagic response through IL-23R-TYK2-STAT3-dependent regulation of intracellular Ca²⁺ level to facilitate mycobacterial clearance in human macrophages

  • Med Microbiol Immunol. 2025 Nov 14;214(1):50. doi: 10.1007/s00430-025-00860-0.
Salina Patel 1,  Mousumi Das 1,  Dev Kiran Nayak 1,  Pramathesh Kumar Dandsena 1,  Mustafeez Ali Quaderi 1,  Amit Mishra 2,  Surajit Das 3,  Ramandeep Singh 4,  Lincoln Naik 5,  Rohan Dhiman 6
Affiliations

Affiliations

  • 1 Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India.
  • 2 Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan, 342011, India.
  • 3 Laboratory of Environmental Microbiology and Ecology, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India.
  • 4 Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurugram Expressway, PO Box # 4, Faridabad, 121001, Haryana, India.
  • 5 Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India. [email protected].
  • 6 Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India. [email protected].
PMID: 41236630 DOI: 10.1007/s00430-025-00860-0
Abstract

Mycobacterium tuberculosis (M. tb), the etiological agent of tuberculosis (TB), subverts host immune responses to establish persistent Infection by influencing cytokine production. An effective and balanced cytokine response is crucial for eliminating the pathogen, whereas disruptions in this balance can lead to increased vulnerability to Infection. Therefore, developing immunomodulatory agents to steer host immunity toward the adequate clearance of M. tb offers a promising strategy for limiting TB. This study investigates the immunomodulatory effects of Furamidine in response to regulating mycobacterial Infection in differentiated THP-1 cells by activating Interleukin-23 (IL-23) signaling. Initially, we checked the immunoregulatory effect of Furamidine and found a substantial increase in the expression of IL-23 at mRNA and protein levels in uninfected and mycobacteria-infected dTHP-1 cells. Neutralization of IL-23 led to a rise in Bacterial survival in the cells, confirming the physiological role of IL-23 in clearing mycobacteria in Furamidine-treated macrophages. It was further elucidated that Furamidine increased the receptors IL-12Rβ1 and IL-23R, essential for IL-23 signaling. IL-23R activation, in turn, phosphorylated its downstream effectors Tyk2 and STAT3, which regulated the intracellular CA2+ level. Neutralization of IL-23 or pharmacological inhibition of Tyk2 and STAT3 by Deucravacitinib and Stattic hampered the process of Autophagy by hindering the IL-23 signaling and leading to an increase in the survival of mycobacteria, pointing to the essential role of IL-23 in response to mycobacteria elimination from the cells. These findings revealed that Furamidine promotes host defense in mycobacterial Infection by enhancing IL-23-mediated Autophagy via the IL-23R/pTYK2/pSTAT3-Ca²⁺ pathway.

Keywords

Autophagy; Ca2+; Furamidine; IL-23; Mycobacteria; TYK2/STAT3.

Figures
Products