Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans

Abstract

BACKGROUND. Cardiovascular disease occurs at lower incidence in premenopausal females compared with age-matched males. This variation may be linked to sex differences in inflammation. We prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males.METHODS. We performed 2 clinical studies in healthy volunteers. In 12 men and 12 women, we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD). In a further 8 volunteers of each sex, we assessed FMD response to glyceryl trinitrate (GTN) at baseline and at 8 hours and 32 hours after typhoid vaccine. In a separate study in 16 men and 16 women, we measured inflammatory exudate mediators and cellular recruitment in cantharidin-induced skin blisters at 24 and 72 hours.RESULTS. Typhoid vaccine induced mild systemic inflammation at 8 hours, reflected by increased white cell count in both sexes. Although neutrophil numbers at baseline and 8 hours were greater in females, the neutrophils were less activated. Systemic inflammation caused a decrease in FMD in males, but an increase in females, at 8 hours. In contrast, GTN response was not altered in either sex after vaccine. At 24 hours, cantharidin formed blisters of similar volume in both sexes; however, at 72 hours, blisters had only resolved in females. Monocyte and leukocyte counts were reduced, and the activation state of all major leukocytes was lower, in blisters of females. This was associated with enhanced levels of the resolving lipids, particularly D-resolvin.CONCLUSIONS. Our findings suggest that female sex protects against systemic inflammation-induced endothelial dysfunction. This effect is likely due to accelerated resolution of inflammation compared with males, specifically via neutrophils, mediated by an elevation of the D-resolvin pathway.TRIAL REGISTRATION. ClinicalTrials.gov NCT01582321 and NRES: City Road and Hampstead Ethics Committee: 11/LO/2038.FUNDING. The authors were funded by multiple sources, including the National Institute for Health Research, the British Heart Foundation, and the European Research Council.

Identification and Profiling of Specialized Pro-Resolving Mediators in Human Tears by Lipid Mediator Metabolomics

“…Thus, the profiling of SPM and these lipid mediators as in Figures 1–7 are definitive in both identity and relative relationships for each SPM-LM signature. Recently, sex differences for resolvins in skin blisters of human exudates have been demonstrated [31]. In the present report, male emotional tears appear to display both SPM and pro-inflammatory eicosanoid mediators, whereas emotional tears from women demonstrated mainly arachidonic acid-derived mediators including the proresolving mediators from this metabolome, namely lipoxins as well as 17-HDHA from DHA and prostaglandins (Table 3).…”

Circulating inflammation-resolving lipid mediators RvD1 and DHA are decreased in patients with acutely symptomatic carotid disease

“…Resolvins are endogenous inflammation-resolving lipid mediators that are triggered by inflammation, likely as a self-defense action. In instances where resolvins are not adequately expressed, a pro-inflammatory state dominates[2, 27–29]. Furthermore, in the case of atherosclerosis, inflammation is a component that is associated with the development of atherosclerotic plaque rupture [1, 2].…”

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors

“…In females, reduced ocular lymph node LXA 4 correlates with increase in the number of T effector cells (T H 1 and T H 17), decrease in regulatory T cells (T reg ) and increase in dry eye pathogenesis (Gao et al, 2015). Sex differences in resolution mechanism in inflammation are also observed in humans, where healthy females on skin challenge produce higher levels of D-series resolvins than males that is associated with accelerated resolution (Rathod et al, 2016). These results suggest that specific SPM may prevent autoimmunity (Gao et al, 2015; Rathod et al, 2016) and link resolution to T cell responses (Chiurchiu et al, 2016).…”

“…Sex differences in resolution mechanism in inflammation are also observed in humans, where healthy females on skin challenge produce higher levels of D-series resolvins than males that is associated with accelerated resolution (Rathod et al, 2016). These results suggest that specific SPM may prevent autoimmunity (Gao et al, 2015; Rathod et al, 2016) and link resolution to T cell responses (Chiurchiu et al, 2016). In obese women, supplementation with n-3 PUFA increases systemic resolvins and upregulation of resolvin receptors (Polus et al, 2016), suggesting that, in humans, failed resolution can be rescued.…”