IL‐37 Expression is Upregulated in Patients with Tuberculosis and Induces Macrophages Towards an M2‐like Phenotype

Interleukin‐37 (IL‐37), a member of the IL‐1 family, primarily functions as an anti‐inflammatory cytokine, reducing inflammation and suppressing the immune response. However, the expression and role of IL‐37 in tuberculosis (TB) remains unknown. We aimed to measure serum levels of IL‐37 and several important cytokines in 25 patients with active TB and to analyse their association with disease activity. We found that IL‐37 levels decreased in patients with TB and recovered after treatment. IL‐37 levels negatively correlated with the serum concentration of IFN‐γ and IL‐12 but positively correlated with IL‐10 and TGF‐β levels. After IL‐37, secretion was blocked in peripheral blood mononuclear cells from active patients with TB, IFN‐γ and IL‐10 production was significantly upregulated; this was not observed in healthy donors or patients after treatment. IL‐37 knockdown significantly enhanced the phagocytic activity of THP1‐derived macrophages towards Mycobacterium tuberculosis (M. tb). M1/M2 polarization‐associated markers were detected simultaneously, and IL‐37 induced a phenotypic shift in THP1‐derived macrophages towards a high CD206⁺ and low CD86⁺ macrophage subtype. Furthermore, this phenotypic shift was accompanied by upregulated mRNA levels of arginase 1, TGF‐β and IL‐10, which are characteristic hallmarks of M2 macrophages. In conclusion, our results suggest that increased levels of IL‐37 in patients with TB are associated with IFN‐γ, IL‐12, IL‐10 and TGF‐β levels and that IL‐37 plays a pathological role in TB infection by inhibiting the production of pro‐inflammatory cytokines and inducing macrophages towards an M2‐like phenotype. Thus, IL‐37 may be a novel research target to understand the pathogenesis of TB infection.