It is widely acknowledged that males and females exhibit contrasting degrees of susceptibility to infectious and non-infectious inflammatory diseases. This is particularly observed in respiratory diseases where human males are more likely to be affected by infection-induced acute inflammations compared to females. The type and magnitude of the innate immune inflammatory response play a cardinal role in this sex bias. Animal models mimicking human respiratory diseases have been used to address the biological factors that could explain the distinct outcomes. In this review, we focus on our current knowledge about experimental studies investigating sex-specific differences in infection-induced respiratory diseases and we provide an update on the most important innate immune mechanisms that could explain sex bias of the inflammatory response. We also discuss whether conclusions drawn from animal studies could be relevant to human.

Group B streptococcus (GBS) is a human pathogenic bacteria inducing a strong inflammatory response that may be detrimental for host tissues if not finely regulated. The inflammatory response can be modulated by different molecular mechanisms, among which growing evidences point toward the crucial role of microRNAs. Regarding innate inflammatory response, studies have reported that miR-223 is essential for the control of granulocyte proliferation and activation. Moreover, number of investigations on miRNA expression profiling performed in various inflammatory settings reveal that miR-223 is among the top differentially expressed miRNA. Yet, the dynamic pattern of expression of miR-223 in vivo with respect to the evolution of the inflammatory process, especially in microbial infection, remains elusive. In this study, we analyzed the kinetic expression of miR-223 in an inflammatory model of GBS-induced murine pneumoniae and looked for correlates with inflammatory markers including innate cell infiltrates. We found that miR-223 expression is rapidly induced at very early time points (3-6 h post infection) mainly by lung infiltrating neutrophils. Interestingly, the level of miR-223 accumulating in the lungs remains higher at later stages of infection (24h and 48h pi) and this correlates with reduced expression of primary inflammatory cytokines and chemokines and with a shift in infiltrating monocyte and macrophage subtypes toward regulatory phenotype. Transient inhibition of miR223 by an antagomir resulted in significant increase of CXCL2 expression and partial enhancing of infiltrating neutrophils in GBS infected lung tissues. This suggests the potential contribution of miR-223 to the resolution phase of GBS-induced acute inflammation.

Previous studies have reported sex disparity in cystic fibrosis (CF) disease, with females experiencing more pulmonary exacerbations and frequent microbial infections resulting in shorter survival expectancy. This concerns both pubertal and prepubertal females, which is in support to the prominent role of gene dosage rather than the hormonal status. The underlying mechanisms are still poorly understood. The X chromosome codes for a large number of micro-RNAs (miRNAs) that play a crucial role in the post-transcriptional regulation of several genes involved in various biological processes, including inflammation. However, their level of expression in CF males and females has not been sufficiently explored. In this study, we compared in male and female CF patients the expression of selected X-linked miRNAs involved in inflammatory processes. Cytokine and chemokine profiles were also evaluated at both protein and transcript levels and cross-analyzed with the miRNA expression levels. We observed increased expression of miR-223-3p, miR-106a-5p, miR-221-3p and miR-502-5p in CF patients compared to healthy controls. Interestingly, the overexpression of miR-221-3p was found to be significantly higher in CF girls than in CF boys and this correlates positively with IL-1β. Moreover, we found a trend toward lower expression in CF girls than in CF boys of suppressor of cytokine signaling 1 (SOCS1) and the ubiquitin-editing enzyme PDLIM2, two mRNA targets of miR-221-3p that are known to inhibit the NF-κB pathway. Collectively, this clinical study highlights a sex-bias in X-linked miR-221-3p expression in blood cells and its potential contribution to sustaining a higher inflammatory response in CF girls.

While number of studies have shown that biological sex is a risk factor in the incidence and severity of infection-induced inflammatory diseases, the underlying mechanisms are still poorly understood. In this study, we compared the innate inflammatory response in male and female mice with group B streptococcal (GBS)-induced pneumoniae. Although male and female mice displayed similar bacterial burdens, males exhibited more innate inflammatory cytokines and chemokines and a higher proportion of infiltrating monocytes/macrophages. The analysis of the distribution of macrophage subtypes M1 (pro-inflammatory) versus M2 (anti-inflammatory) yielded a higher M1/M2 ratio in infected males compared with females. Given the importance of the chromosome X-linked microRNA-223-3p (miR-223-3p) in modulating the inflammatory process and macrophage polarization, we investigated its potential contribution in sex bias of GBS-induced innate inflammatory response. Knock-down of miR-223-3p with specific antagomiR resulted in increased inflammatory response and higher M1/M2 ratio following GBS infection. Notably, compared to male mice, we detected higher amount of miR-223-3p in macrophages from females that correlated negatively with M1 phenotype. These results suggest that differential expression of miR-233-3p may impact macrophage polarization, thereby contributing to fine-tune sex differences in inflammatory response.