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.

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 Ca