Host-Mediated Antimicrobial Effects and NLRP3 Inflammasome Modulation by Caulerpin and Its Derivatives in Macrophage Models of Mycobacterial Infections

Caulerpin, a bis-indole alkaloid isolated from <i>Caulerpa racemosa</i>, has several documented pharmacological activities, including antineoplastic and antiviral properties. This study aimed to evaluate the anti-inflammatory and anti-tubercular potentials of caulerpin and its analogues in RAW 264.7 macrophages infected with <i>Mycobacterium</i> spp. Additionally, we evaluated cytokine production and NLRP3 expression in this infection model. Toxicity tests were performed using Vero E6 and HepG2 cell lines and <i>Artemia salina</i>. Pre-incubation of RAW 264.7 cells with caulerpin and its analogues decreased internalized <i>M. smegmatis</i> and <i>M. tuberculosis</i> H37Ra. Furthermore, treatment of <i>M. smegmatis</i>-infected macrophages with caulerpin and its analogues reduced bacterial loads. Caulerpin reduced the CFU count of internalized bacilli in the <i>M. tuberculosis</i> H37Ra infection model. In addition, caulerpin and its diethyl derivative were notably found to modulate IL-1β and TNF-α production in the <i>M. smegmatis</i> infection model after quantifying pro-inflammatory cytokines and NLRP3. Caulerpin and its derivates did not affect the viability of Vero E6 and HepG2 cell lines or nauplii survival in toxicity studies. These findings demonstrate that caulerpin and its analogues exhibit anti-inflammatory activity against <i>Mycobacterium</i> spp. infection in RAW 264.7 macrophages and show promising potential for further efficacy and safety evaluation.