Sex differences in structural cell-mediated immune regulation: Implications for precision respiratory medicine

Abstract

For a long time, sex dimorphism has been recognised as an important factor modulating immune function in health and disease across the lifespan, contributing to disparities in epidemiology, pathophysiology, clinical manifestations, progression and therapeutic outcomes across multiple diseases. Respiratory diseases such as pulmonary arterial hypertension (PAH), pneumonia, and asthma exhibit notable sex differences in incidence and prognosis, yet the underlying mechanisms remain incompletely understood. In the respiratory system, investigating how structural cells respond to sex hormone signals and elucidating their sex dimorphism in gene expression and secretion of immune mediators may help elucidate the complexities of sex-dimorphic immune homeostasis in both physiological and pathological circumstances (Figure 1). Such insights are essential for establishing a foundation for precision medicine strategies tailored to sex-based considerations in clinical practice.

Epithelial cells constitute the primary protective barrier at key host-environment interfaces, including the respiratory and gastrointestinal tracts, skin, and glands. Beyond serving as a physical barrier, they actively orchestrate local immune responses against pathogens and harmful substances, and directly coordinate tissue repair and regeneration through cellular proliferation and extracellular matrix remodelling.^[1] During lung development, sex hormones are key regulators of alveolar epithelial maturation, significantly influencing the production of pulmonary surfactant, which is critical for gas exchange and structural integrity. In adult mice, ovariectomy-induced oestrogen deficiency results in a marked reduction in alveolar number and surface area, a detrimental effect reversible with exogenous oestrogen supplementation, underscoring the hormone's role in maintaining lung parenchymal structure.^[2] Oestrogen also upregulates the expression and surface abundance of epithelial sodium channel following lipopolysaccharide challenge via activation of the phosphatidylinositol 3-kinase/protein kinase B/serum glucocorticoid regulated kinase 1 pathway, thereby mitigating pulmonary inflammation and lung oedema.^[3] In contrast, androgens generally suppress alveolar epithelial function, with effects that exhibit clear sexual dimorphism. For instance, dihydrotestosterone was found to inhibit sodium transport exclusively through non-classical, receptor-independent pathways in foetal distal lung epithelial cells from male rats, an effect not reversed by the androgen receptor antagonist flutamide (Table 1).^[4]

Airway epithelial cells release interleukin (IL)-33 upon allergen exposure, initiating type 2 immunity, activating group 2 innate lymphoid cells (ILC2s), and inducing IL-13 secretion to drive airway inflammation. This epithelial-ILC2 axis, differentially regulated by sex hormones, underlies sex disparities in pulmonary diseases. In females, airway epithelial cells, regulated by oestrogen-activated oestrogen receptors, enhance IL-33 release and amplify type 2 inflammation;^[5] while oestrogen slightly suppresses ILC2 cytokine production via nuclear factor kappa-B pathway modulation,^[6] its net effect is pro-inflammatory. In males, airway epithelial cells, regulated by androgens, reduce IL-33/Thymic stromal lymphopoietin expression and indirectly decrease ILC2 numbers/IL-5/IL-13 secretion,^[7] achieving double inhibition of inflammation. Furthermore, drug responses targeting epithelial pathways also vary by sex. Dupilumab, an IL-4 receptor α blocker that acts on airway epithelial cells to suppress type 2 inflammation, elicits stronger clinical remission in males with severe asthma than in females. Multivariate analysis identified male sex as an independent predictor of treatment success,^[8] indicating that biological sex differences, potentially mediated by sex-specific regulation of IL-4 receptor α expression or downstream signalling, directly influence structural cell responsiveness to targeted therapy and contribute to divergent clinical outcomes. This finding offers compelling evidence supporting sex-specific precision medicine (Table 1).

Endothelial cells play a significant role in maintaining microenvironmental homeostasis by regulating vascular tone, permeability, and selective substance exchange. However, research on sex-based differences in endothelial biology remains limited. PAH demonstrates marked sex dimorphism, with higher incidence in females but better survival—a phenomenon termed the “oestrogen paradox”.^{[9, 10]} Recent studies indicate that sex-related differences in endothelial metabolism and function may underlie this disparity. For example, the oestrogen metabolite 16α-hydroxyestrone suppresses SRY-related HMG-box 17 expression in endothelial cells via oestrogen receptor α, impairing mitochondrial energy metabolism and aggravating PAH progression,^[10] providing direct molecular evidence for sex-dimorphic structural cell contributions to disease. Sex differences are also evident in infectious contexts: female COVID-19 patients generally experience less severe outcomes than males, and postmenopausal women show elevated risk, implying a protective role for oestrogen. Mechanistically, oestrogen downregulates the expression of angiotensin-converting enzyme 2, the primary SARS-CoV-2 entry receptor, in human umbilical vein endothelial cells, thereby limiting viral entry.^{[11, 12]} Meanwhile, a recent study revealed profound sex dimorphism in immune checkpoint regulation in these cells. Specifically, the upregulation of programmed death ligand 1 and release of vascular endothelial growth factor (VEGF) occurred only in female-derived cells. Anti-VEGF agents such as bevacizumab and sunitinib suppressed this female-specific response,^[13] underscoring the potential for sex-informed combination therapies that concurrently target VEGF and programmed cell death protein 1/programmed death-ligand 1 axes to enhance anti-tumour immunity in female patients (Table 1).

Smooth muscle cells serve as the primary effector of bronchoconstriction and a key contributor to airway remodelling. However, the intrinsic sex differences in smooth muscle cell function and its regulation by sex hormones remain poorly understood. Recently, studies show that androgen receptor activation by testosterone or dihydrotestosterone blunts the genomic enhancement of intracellular calcium in airway smooth muscle cells, contributing to the alleviation of airway hyperresponsiveness.^[14] Meanwhile, progesterone via its receptor reverses IL-6-induced pulmonary artery smooth muscle cells proliferation by interacting with signal transducer and activator of transcription 3 and retaining it in the cytoplasm, thereby reducing transcription of pro-proliferative genes.^[15] Collectively, these findings establish smooth muscle cell as a direct target of sex hormone action in the context of IL-driven inflammation, contributing to the sex-specific pathophysiology of respiratory diseases (Table 1).

Sex dimorphism is also evident in fibroblasts. While elevated extracellular matrix stiffness is a defining feature of fibrosis, activated oestrogen receptor signalling has been found to counteract this process. It does so by interrupting the mechanotransduction feedback loop that would otherwise sustain fibrotic signalling, even after the reduction of mechanical stiffness.^[16] This discovery unveils a novel layer of mechanochemical regulation in the development of sex-biased fibrosis. Not only that, in vitro, female-derived fibroblasts were observed to produce approximately 2-fold higher levels of IL-6 compared to their male counterparts.^[17] This finding points to an intrinsic, hormone-independent sex dimorphism in fibroblast function. Collectively, these findings demonstrate that fibroblasts exhibit sex dimorphism across hormone-dependent signalling pathways as well as intrinsic innate immune mechanisms. This multifaceted sex bias highlights fibroblasts as another promising cellular target for precision medicine in pulmonary diseases (Table 1).

In summary, this review has highlighted how sex differences, mediated through structural cells, contribute to respiratory disease pathophysiology and therapeutic heterogeneity. In addition, there are many newly discovered mechanisms that also regulate sex dimorphism, such as the X-linked expression of toll-like receptor 7 and its ability to escape X-chromosome inactivation, which can enhance women's antiviral immune function. However, toll-like receptor 7-mediated effects are primarily associated with immune cells, including B cells, macrophages and dendritic cells.^[18] The mechanism of its action in structural cells still needs further exploration. Moving forward, mechanism research should be conducted in this field to delineate cell-type-specific sex hormone signalling networks through technologies such as single-cell omics and spatial transcriptomics. It will also be essential to explore the contributions of sex-chromosome-linked genes and the crosstalk between hormonal and microenvironmental signals. Importantly, preliminary evidence of sex-biased treatment responses should be validated through prospective, sex-stratified clinical trials. Only through such concerted efforts can we realise the full potential of sex-specific diagnostic and therapeutic strategies, ultimately advancing a more equitable and effective era of precision respiratory medicine.

Quocdai Vu and Wei Gao wrote the original manuscript. Wujian Xu and Ximing Liao reviewed the manuscript. Qiang Li supervised the project and was responsible for funding acquisition.

The authors declare no conflict of interest.

This work was supported by the National Natural Science Foundation of China (grant number: 82270116) for Qiang Li; the National Natural Science Foundation of China (grant number: 82570119), the Natural Science Foundation of Shanghai (grant number: 25ZR1402443), Healthcare Talents Youth Program of Shanghai Pudong New Area (grant number: 2025PDWSYCQN-02) for Wei Gao.

Not applicable for an invitation letter.