Modulation of IL-1, IL-6 and IL-18 cytokine signaling in animal models of atherosclerosis: a systematic review evaluating animal sex in preclinical research

Targeting of IL-1, IL-6 and IL-18 signaling is a main focus of anti-inflammatory therapy development against atherosclerosis. In preclinical atherosclerosis studies, animal sex may however affect therapeutic efficacy. Evidence for this hypothesis is lacking. We therefore aimed to study sex used and influence of animal sex on therapeutic efficacy of IL-1, IL-6 and IL-18 pathway interventions in atherosclerosis animal models. Medline (PubMed) and EMBASE (OVID) were comprehensively searched and screened to identify studies investigating the effects of targeting IL-1, IL-6 and IL-18 signaling in atherosclerosis animal models. Study characteristics and plaque size data were extracted. Individual effect sizes were calculated and pooled using the random effects model. Predefined subgroup analyses for sex were conducted. From 1744 retrieved studies, 62 papers were included in this systematic review, of which 47 papers in the meta-analyses. All 47 studies used mice, of which 41 investigated inhibitory interventions and 8 stimulatory. Meta-analyses showed a significantly smaller plaque size upon inhibition of cytokine signaling (SMD: -1.5 [-1.8 to -1.2], n = 39) and a significantly larger plaque upon stimulation (SMD: 1.2 [0.3 to 2.1], n = 8). The majority of the studies included male mice. Due to the limited number of studies with females, subgroup analysis for sex could only be performed for males and revealed no differences compared to the overall analyses, suggesting that male mice are suitable for such studies. More studies with female mice are required to truly assess whether animal sex is a variable in treatment efficacy of IL-1, IL-6 and IL-18 pathway interventions in atherosclerosis.