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Review
. 2024 May 21:15:1379754.
doi: 10.3389/fimmu.2024.1379754. eCollection 2024.

Sex-related immunity: could Toll-like receptors be the answer in acute inflammatory response?

Alexandros Popotas  1   2 , Georges Jacques Casimir  1   3 , Francis Corazza  2   4 , Nicolas Lefèvre  1   3
Affiliations
Review

Sex-related immunity: could Toll-like receptors be the answer in acute inflammatory response?

Alexandros Popotas et al. Front Immunol. .

Abstract

An increasing number of studies have highlighted the existence of a sex-specific immune response, wherein men experience a worse prognosis in cases of acute inflammatory diseases. Initially, this sex-dependent inflammatory response was attributed to the influence of sex hormones. However, a growing body of evidence has shifted the focus toward the influence of chromosomes rather than sex hormones in shaping these inflammatory sex disparities. Notably, certain pattern recognition receptors, such as Toll-like receptors (TLRs), and their associated immune pathways have been implicated in driving the sex-specific immune response. These receptors are encoded by genes located on the X chromosome. TLRs are pivotal components of the innate immune system, playing crucial roles in responding to infectious diseases, including bacterial and viral pathogens, as well as trauma-related conditions. Importantly, the TLR-mediated inflammatory responses, as indicated by the production of specific proteins and cytokines, exhibit discernible sex-dependent patterns. In this review, we delve into the subject of sex bias in TLR activation and explore its clinical implications relatively to both the X chromosome and the hormonal environment. The overarching objective is to enhance our understanding of the fundamental mechanisms underlying these sex differences.

Keywords: TLR-Toll-like receptor; X chromosome; hormones; infection; innate immunity; sepsis; sex; trauma.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
TLR pathways. The TIR domain within TLR2, TLR4, or TLR5 interacts with MyD88, initiating the activation of IRAK1, IRAK4, and TRAF6. This interaction triggers the phosphorylation of the NF-κB complex and instigates NF-κB-regulated factors. Additionally, it activates p38 MAPK and ERK1/2, which subsequently induce AP-1 activity. The activation of NF-κB and AP-1 prompts the production of proinflammatory cytokines. TRIF functions as an adaptor molecule for TLR3 and TLR4, facilitating NF-κB activation through its interaction with TRAF6, while also initiating TBK1 and IKKϵ activation. TBK1 and IKKϵ phosphorylate IRF3, leading to the expression of IFN-a/b. TLR7, TLR8, and TLR9 are implicated in IFN expression through TRIF-independent mechanisms, potentially involving IRF-5 or the MyD88–IRAK1–TRAF6 pathway, although the exact mechanism remains to be elucidated. Created with BioRender.com .
Figure 2
Figure 2
TLR sex differences in humans and rodents. Created with BioRender.com .
Figure 3
Figure 3
The influence of estrogens on TLR expression and activation in human and animal models. Created with BioRender.com .
Figure 4
Figure 4
The influence of progesterone on TLR expression and activation in human and animal models. Created with BioRender.com .
Figure 5
Figure 5
TLR expression and activation across the menstrual cycle. Created with BioRender.com .
Figure 6
Figure 6
X chromosome contribution to TLR sex differences. Created with BioRender.com .
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