Differences in sex mediate prevalence of inflammatory disorders

Author: Lily Thompson

Figure 1. Difference in expression of proinflammatory mediators between male and female derived neutrophils. Although difference in COX-1 expression is insignificant, COX-2 expression is significantly higher in male versus female donors. The addition of 5-lipoxygenase (5-LO) inhibitor MK885 leads to increased PGE2 production in female cells, effectively eliminating the sex dimorphism. 

Link to article: https://www.nature.com/articles/s41598-017-03696-8

Autoimmune diseases, such as rheumatoid arthritis, and inflammatory diseases, such as asthma, have higher incidence in females than males (1). Conversely, immune disorders such as sepsis, post-surgery infection, and atherosclerosis are more commonly observed in males (1)(2). Most notably, premenopausal women seem to be “protected” against cardiovascular disease, which remains the leading cause of death in the United States (3). In fact, heart disease occurs 7 to 10 years later in women than in men (4). Besides pathophysiology, sex may also influence efficacy and adverse effects of therapies (1). Thus, further research into the molecular and cellular mechanisms underlying this difference could present important implications in terms of treatment, more specifically individualized treatment (2).

Prior studies point towards differences in inflammatory response as a possible cause in sex dimorphism. Research group Pace et al. propose that the discrepancy between male and female inflammatory response comes down to differences in production of leukotriene (LT) and prostaglandin (PG), which are two types of eicosanoids. As we learned in BCM 441, eicosanoids are pro-inflammatory molecules that derive from arachidonic acid, and prostaglandin has roles in regulating pain and inflammation. To investigate sex dimorphism during inflammation, Pace et al. performed in vivo experiments using both mice and rats, and in vitro experiments using human cells.

First, in order to observe eicosanoid biosynthesis, the authors injected mice with zymosan, a molecule that induces inflammatory response. Male mice exhibited higher levels of prostaglandin E2 (PGE2) in later phases of inflammation. In contrast, female mice exhibited higher levels of leukotriene C4 (LTC4) in early phase of inflammation, minutes after zymosan injection. The authors then used rats to confirm their observations in a second model of acute inflammation. Carrageenan, a pro-inflammatory agent, was injected into the rats to induce inflammatory response. Consistent with the murine model, a couple hours after induction, female rats exhibited higher levels of LTC4 than males and the opposite trend was observed for PGE2 levels, confirming that sex differences exist in vivo in two different animal models. The fact that PG levels were significantly higher in males, while LT levels were higher in females, indicates a greater conversion of arachidonic acid to LT in females and arachidonic acid to PG in males.

The authors next sought to determine whether the higher levels of PGE2 production in males was simply due to a higher number of PGE2 producing cells, in other words neutrophil count. These innate immune cells are constantly in circulation and, when primed, synthesize and secrete prostaglandins and leukotrienes, among other molecules (5). However, 4 hours after induction of inflammatory response, a cell count revealed no difference in the number of neutrophils in males versus females. Thus, the authors turned towards COX-1 and COX-2 expression, both key enzymes in the biosynthesis of PGs. While no difference was observed in COX-1 levels, COX-2 expression was higher in male cells, indicating a possible role for this enzyme. In addition experiments, the authors explored whether a shunting phenomena might contribute to the difference in PG levels. From arachidonic acid, LT and PG are synthesized via two separate pathways with the main molecules mediating each pathway 5-LO and COX-1/2 respectively. To explore whether difference may be due to pathway, the authors blocked 5-LO production using MK886, a pharmacological inhibitor of the enzyme, and found that this successfully cleared the sex difference in PGE2 levels by increasing PG production in females.

To investigate whether the sex dimorphism exists in a similar manner in humans, the authors extracted neutrophils from the blood of female and male donors and stimulated them with LPS, which are large molecules found on the outside of gram negative bacteria that induce strong immune response. They observed that formation of PGE2 following stimulation was much greater in male neutrophils than in female neutrophils. Furthermore, in the human cells, COX-2 expression was greater in males than in females, consistent with the in vivo studies. Lastly, human neutrophils treated with MK886 also exhibited an abolition of the sex difference (Figure 1).

In summary, the pro-inflammatory molecules in this study are produced from arachidonic acid and can come from two pathways: 1) a COX-mediated cascade, which leads to prostaglandins, and 2) a 5-LO-mediated cascade, which generates leukotrienes. The authors found that by blocking the 5-LO medicated cascade with MK886, arachidonic acid is redirected towards the COX-mediated cascade. This results in removal of the sex difference by significantly increasing levels of PGE2 in females. However, while the authors were able to determine that a sex difference does in fact exist, the exact biochemical and molecular mechanisms remain unclear. In future studies, it would be interesting to see more of a focus on the biochemical mechanism behind the dimorphism.

Neutrophils from male donors produce higher levels of PG, which appears to be a consequence of greater COX-2 expression. This finding may help explain, in part, the sex dimorphism seen in certain innate immune disorders. One drug of interest mentioned by the authors, which was also touched upon in BCM 441, is aspirin (1). Research suggests that aspirin is metabolized differently depending on sex, which aligns with what’s known about aspirin’s mechanism of action (inhibits COX-1/2, the latter of which is differentially expressed in males and females). Finally, additional research into how certain diseases change depending on sex and whether it would be possible to delay the onset of certain sex related diseases by modifying levels of proinflammatory mediators could be useful. 

References

  1. Pace et al. (Dec 2017). Sex-biased eicosanoid biology: Impact for sex differences in inflammation and consequences for pharmacotherapy. ElsevierDOI: https://doi.org/10.1016/j.bcp.2017.06.128
  2. Fairweather, D. (Apr 2015). Sex Differences in Inflammation during Atherosclerosis. Sage Journals. DOI: http://journals.sagepub.com/doi/abs/10.4137/CMC.S17068
  3. Rathod et al. (Feb 2017). Sex differences in the inflammatory response and inflammation-induced vascular dysfunction. The Lancet. DOI: https://doi.org/10.1016/S0140-6736(17)30416-6
  4. Mass, A & Appleman, Y. (Dec 2010). Gender differences in coronary heart disease. Neth Heart J. DOI: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3018605/
  5. Write et al. (Mar 2010). Neutrophil function in inflammation and inflammatory diseases. Rheumatology, Vol 49, (9): pp1618–1631 DOI: https://doi.org/10.1093/rheumatology/keq045

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