Nell-1 inhibits lipopolysaccharide-activated macrophages into M1 phenotype through the modulation of NF-κB pathway.

Nel-like molecule-1 (Nell-1), as a novel osteo-inductive molecule with great potential for clinical applications, has various functions including promoting chondrogenesis, suppressing osteoclastic activity, promoting osteogenesis, suppressing inflammation and promoting vascularization. Its anti-inflammatory potential has been widely studied. However, its anti-inflammatory potential in macrophage and possible underlying molecular mechanisms are poorly understood. Therefore, the present study aims to evaluate the anti-inflammatory potential and the regulation to macrophage polarization of Nell-1 in human myeloid cell line (THP-1) derived macrophages. M1-related markers and M2-related markers were studied in THP-1 derived macrophages. The suppressive potential of Nell-1 on lipopolysaccharide (LPS)-induced translocation of nuclear factor-kappa B (NF-κB) in THP-1 macrophage was studied. Results showed that Nell-1 significantly reduced M1 macrophage-related surface marker cluster of differentiation 86 (CD86) and inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) and reversed the LPS-induced M1 polarization of macrophages by upregulating the M2-specific markers of vascular endothelial growth factor (VEGF), arginase-1(Arg-1), and cluster of differentiation 206 (CD206) in vitro. In addition, the possible mechanism of the anti-inflammatory effects of Nell-1 is via regulating NF-κB pathway. Hence, Nell-1 is a potential suppressor of inflammation and is involved in the regulation of macrophage polarization. Nell-1 may be a potential candidate for treating inflammatory diseases and promoting tissue regeneration.