The primary function of chemokines is to direct the migration of leukocytes to the site of injury during inflammation. The effects of chemokines are modulated by several means, including binding to G-protein coupled receptors (GPCRs), binding to glycosaminoglycans (GAGs), and through post-translational modifications (PTMs). GAGs, present on cell surfaces, bind chemokines released in response to injury. Chemokines bind leukocytes via their GPCRs, which directs migration and contributes to local inflammation. Studies have shown that GAGs or GAG-binding peptides can be used to interfere with chemokine binding and reduce leukocyte recruitment. Post-translational modifications of chemokines, such as nitration, which occurs due to the production of reactive species during oxidative stress, can also alter their biological activity. This review describes the regulation of chemokine function by GAG-binding ability and by post-translational nitration. These are both aspects of chemokine biology that could be targeted if the therapeutic potential of chemokines, like CXCL8, to modulate inflammation is to be realised.

Summary Leucocyte recruitment is critical during many acute and chronic inflammatory diseases. Chemokines are key mediators of leucocyte recruitment during the inflammatory response, by signalling through specific chemokine G‐protein‐coupled receptors (GPCRs). In addition, chemokines interact with cell‐surface glycosaminoglycans (GAGs) to generate a chemotactic gradient. The chemokine interleukin‐8/CXCL8, a prototypical neutrophil chemoattractant, is characterized by a long, highly positively charged GAG‐binding C‐terminal region, absent in most other chemokines. To examine whether the CXCL8 C‐terminal peptide has a modulatory role in GAG binding during neutrophil recruitment, we synthesized the wild‐type CXCL8 C‐terminal [CXCL8 (54–72)] (Peptide 1), a peptide with a substitution of glutamic acid (E) 70 with lysine (K) (Peptide 2) to increase positive charge; and also, a scrambled sequence peptide (Peptide 3). Surface plasmon resonance showed that Peptide 1, corresponding to the core CXCL8 GAG‐binding region, binds to GAG but Peptide 2 binding was detected at lower concentrations. In the absence of cellular GAG, the peptides did not affect CXCL8‐induced calcium signalling or neutrophil chemotaxis along a diffusion gradient, suggesting no effect on GPCR binding. All peptides equally inhibited neutrophil adhesion to endothelial cells under physiological flow conditions. Peptide 2, with its greater positive charge and binding to polyanionic GAG, inhibited CXCL8‐induced neutrophil transendothelial migration. Our studies suggest that the E70K CXCL8 peptide, may serve as a lead molecule for further development of therapeutic inhibitors of neutrophil‐mediated inflammation based on modulation of chemokine–GAG binding.

Endometriosis is a chronic condition affecting ~10% of women globally. Little is known about the impact of the coronavirus disease 2019 (COVID-19) pandemic on their care. This brief report is aimed to explore the impact of COVID-19 on the care of people with endometriosis around the world, their priorities in relation to their clinical care during and coming out of the pandemic, and whether they believed that endometriosis makes them more vulnerable to COVID-19. An internet-based survey collected data in five languages between May 11, 2020, and June 8, 2020. Only participants with a surgical or radiological diagnosis of endometriosis aged 18 years or over were included. A total of 6,729 eligible respondents completed the survey with 80.7% [95% CI (79.7, 81.6)] reporting a negative impact on their care. This included difficulties obtaining medication (20.3%), cancelled/postponed gynaecology appointments (50.0%), and cancelled/postponed procedures (37.2%). More than half worried that their endometrioses make them more vulnerable to COVID-19 [54.2%; 95% CI (53.0, 55.4)]. The top three priorities were remarkably consistent around the world: contact with gynaecologists, knowing when procedures would be performed, and support with mental health (20.3% prioritising this aspect during the pandemic and 13.0% as restrictions begin to ease). This study shows the substantial impact the COVID-19 pandemic has had on people with endometriosis and describes how they would like care prioritised moving forwards. The findings regarding significant support needs for mental health add further weight to the growing recognition of attending to such issues as part of good patient-centred care.

Endometriosis is a chronic condition that affects ~10% of women globally. Its symptoms include chronic pelvic pain, heavy periods and tiredness/fatigue, which have been associated with poorer quality of life and mental health. We aim to explore the impact of the COVID-19 pandemic on pain and fatigue symptoms and their interactions with the impact on mental health in people with endometriosis. This global cross-sectional online survey study collected data from 4717 adults with self-reported surgical/radiological diagnosis of endometriosis between May and June 2020. The survey included questions on the current status and changes of endometriosis symptoms (pelvic pain, tiredness/fatigue, and bleeding patterns), mental health, pain catastrophising, and the impact of the COVID-19 pandemic on the respondents’ lives. Compared to 6 months earlier, Respondents reported a marked worsening of their endometriosis symptoms (endometriosis-associated pain (39.3%; 95% CI: 37.7, 40.5), tiredness/fatigue (49.9%; 95% CI: 48.4, 51.2) and bleeding patterns (39.6%; 95% CI: 38.2, 41)) and mental health (38.6%; 95% CI: 37.2, 39.9). Those with a pre-existing mental health diagnosis (38.8%) were more likely to report their symptoms worsening. Worsening of pain and tiredness/fatigue was significantly correlated with worsening of mental health (P < 0.001). The relationship between changes in mental health and (a) change in pain and (b) change in fatigue was found to be weakly mediated by pain catastrophising scores (pain: B = 0.071, lower limit of confidence interval (LLCI) = 0.060, upper limit of confidence interval (ULCI) = 0.082, tiredness/fatigue: B = 0.050, LLCI = 0.040, ULCI = 0.060). This study demonstrates that stressful experiences impact the physical and mental health of people with endometriosis. The findings highlight the need to consider psychological approaches in the holistic management of people with endometriosis. Lay summary Endometriosis is a chronic condition in which tissue similar to that of the lining of the womb grows outside it. It affects around 10% of women globally, and the symptoms often include persistent pelvic pain, heavy periods and tiredness/fatigue. These symptoms are associated with impaired mental health and life quality. This study used an online questionnaire to assess the experiences of people with endometriosis during the first months of the pandemic. Results from 4717 adults revealed that pelvic pain, tiredness/fatigue and bleeding worsened in more than 39% of the participants. Poor mental health was also exacerbated and associated with worsening in tiredness/fatigue. Further analysis revealed that this relationship could be partially explained by ‘pain catastrophising’, which measures how participants think about their pain. Our results suggest that stressful experiences like the pandemic negatively impact the already burdened mental health of people with endometriosis, who could benefit from psychological interventions.