Restoration of Treg function and polarization of M2 macrophages by tofacitinib to alleviate sarcoidosis through the mediation of the JAK3/STAT5 pathway.

OBJECTIVE

Sarcoidosis is a multisystem granulomatous syndrome with a wide range of clinical features. Tofacitinib, a JAK inhibitor, may become a new treatment for sarcoidosis. The study aimed to elucidate how tofacitinib modulates immune responses and reduces granuloma formation in SodA-induced sarcoidosis.

METHODS

To evaluate the effects of tofacitinib on granuloma formation, sarcoidosis was induced using SodA peptide, and tofacitinib was administered. The activation of JAK/STAT signaling, pyroptosis, and Th1/Th17/regulatory T cells (Treg) immune profile were detected. Macrophages and Treg were isolated and co-cultured to verify Treg's influence on macrophage polarization.

RESULTS

Tofacitinib reduced granulomas in SodA-induced sarcoidosis. It suppressed the activation of JAK3/STAT5 signaling and induced pyroptosis, as evidenced by increased cleaved-Gasdermin D (P = 0.006). Tofacitinib increased the proportions of both M1 and M2-like macrophages, with a predominant shift toward M2-like polarization (P = 0.0014). Notably, tofacitinib restored the ability of Treg cells to induce M2 anti-inflammatory macrophage polarization, leading to reduced IL-1β secretion (P = 0.0183). In addition, tofacitinib reduced the proportions of both Th17 and Treg cells (Th17: P = 0.0022; Treg: P = 0.0021). It did not significantly affect STAT1 or AKT activation.

CONCLUSION

Tofacitinib treatment holds potential for mitigating granulomas, likely mediated through the JAK3/STAT5 signaling pathway and the induction of pyroptosis. Furthermore, tofacitinib therapy re-establishes equilibrium within the Th1/Th2/Treg/Th17 immune cell profile, restores the functional capacity of Tregs, and promotes a tendency towards M2 macrophage polarization. These insights contribute to a more comprehensive understanding of the immunomodulatory effects of tofacitinib in the context of sarcoidosis treatment.