Squalene targets pro- and anti-inflammatory mediators and pathways to modulate over-activation of neutrophils, monocytes and macrophages

•Squalene has anti-inflammatory activities on LPS-mediated inflammatory response.•Squalene targets pro-inflammatory mediators such as TLR4, iNOS, COX-2 or MPO.•Squalene enhanced expression of anti-inflammatory enzymes (HO-1).•Squalene modulated Nrf2, NF-κB, MAPKs, MMPs and PPARγ signalling pathways.•Squalene prevents the over-activation of neutrophils/monocytes/macrophages. Squalene is a natural triterpene consumed as an integral part of the human diet. Increasing evidence demonstrates that squalene has antioxidant, cardioprotective and anti-carcinogenic activities. Nevertheless, its anti-inflammatory properties remain unclear. The effects of squalene on lipopolysaccharide (LPS)-mediated inflammatory response in murine macrophages and human monocytes and neutrophils were investigated. Squalene reduced intracellular levels of ROS, nitrites, cytokines (TNF-α, IL-1β, IL-6 and IFN-γ) and pro-inflammatory enzymes (iNOS, COX-2 and MPO), including a decreased expression of TLR4 and key proteins for signalling pathways mediated by NF-κB (IκBα), MAPKs (JNK) and MMPs (1, 3 and 9). In addition, squalene enhanced expression levels of anti-inflammatory enzymes (HO-1) and transcription factors (Nrf2 and PPARγ). This study establishes that squalene has significant potential for management of inflammatory conditions characterized by an over-activation of neutrophils/monocytes/macrophages and thereby for the efficient termination of the inflammatory response.