Farmacología Aug 18, 2026

Innate immunity: current understandings and future perspectives

Figura científica PMC{$pmc_id}
Key discoveries in innate immunity. The historical trajectory of seminal discoveries in innate immunity is delineated. The journey began in the 1880s with the identification of phagocytes capable of actively engulfing foreign particles, establishing the cellular foundation of innate immunity. This was followed by the discovery of the DCs and NKs, the elucidation of the complement system, the proposal and subsequent validation of the PRR paradigm, and the discovery of pivotal signaling pathways. The narrative extends to recent conceptual advancements, including the proposal of trained immunity and the emerging concept of ancestral immunity. This figure was created with BioRender (http://biorender.com/)
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Sex-Dimorphic Signaling Architecture in Innate Immunity: Molecular Mechanisms, Organellar Crosstalk, and Precision Immunopharmacology



Abstract


The innate immune system serves as the primary line of defense against pathogen invasion and cellular stress, operating through a sophisticated network of pattern recognition receptors (PRRs), intracellular signaling cascades, and organellar communication. Recent advances in molecular immunology have illuminated the critical role of organelle dysfunction—specifically mitochondrial ROS production, cytosolic release of mitochondrial DNA (mtDNA), and lysosomal membrane permeabilization—in orchestrating canonical pathways such as cGAS-STING, TLR-MyD88/TRIF, and NLRP3 inflammasome activation. Concurrently, Sex-and-Gender-Based Analysis (SGBA) has emerged as a fundamental paradigm in precision immunopharmacology. Biological sex profoundly shapes innate immune responsiveness through X-chromosome gene dosage effects (including incomplete X-inactivation of *TLR7* and *IRAK1*) and differential steroid hormone signaling (17β-estradiol versus androgen receptor axis activation). These sex-dimorphic dynamics drive disparate disease trajectories: females exhibit heightened antiviral resistance and enhanced vaccine responsiveness alongside an elevated susceptibility to autoimmune pathologies, whereas males show increased vulnerability to severe acute inflammation and sepsis. This review synthesizes current mechanistic insights into innate immune activation, details sex-dimorphic regulatory mechanisms, and provides strategic frameworks for translating these biological divergences into sex-informed immunotherapeutic strategies.

Introduction & Cellular Mechanisms



The innate immune system recognizes evolutionary conserved molecular motifs known as Pathogen-Associated Molecular Patterns (PAMPs) and host-derived Damage-Associated Molecular Patterns (DAMPs). This surveillance is mediated by germline-encoded Pattern Recognition Receptors (PRRs), which broadly categorize into transmembrane receptors—such as Toll-like Receptors (TLRs) and C-type Lectin Receptors (CLRs)—and cytosolic sensors, including RIG-I-like Receptors (RLRs), AIM2-like Receptors (ALRs), and Nucleotide-binding Oligomerization Domain (NOD)-like Receptors (NLRs).

```
[ Extracellular Space ]
PAMPs / DAMPs
│
┌──────┴──────┐
▼ ▼
[TLR4] [TLR7/8] (Endosomal)
│ │
MyD88 MyD88
│ │
├─────────────┴──────────┐
▼ ▼
[NF-κB] [IRF7]
(Pro-inflammatory) (Type I IFNs)
```

At the cell surface and within endosomal compartments, canonical TLR signaling bifurcates into two major pathways:
1. The MyD88-Dependent Pathway: Utilized by all TLRs except TLR3, MyD88 recruitment leads to the assembly of the "myddosome" complex containing IRAK4 and IRAK1/2. This triggers the activation of the IκB kinase (IKK) complex, driving the nuclear translocation of Nuclear Factor kappa B (NF-κB) and Transactivation of pro-inflammatory cytokines such as TNF-α, IL-6, and pro-IL-1β.
2. The TRIF-Dependent Pathway: Engaged by TLR3 and endocytosed TLR4, TRIF (Toll/IL-1R domain-containing adapter-inducing interferon-β) associates with TRAF3 and TBK1 (TANK-binding kinase 1), inducing the phosphorylation and nuclear accumulation of Interferon Regulatory Factors 3 and 7 (IRF3/7). This drives the transcription of Type I Interferons (IFN-α/β).

Cytosolic DNA sensing is governed primarily by the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) axis. Upon binding double-stranded DNA (dsDNA), cGAS synthesizes 2'3'-cGAMP, which binds STING at the endoplasmic reticulum (ER) membrane. STING undergoes conformational oligomerization, translocating to the ER-Golgi intermediate compartment (ERGIC) to activate TBK1 and NF-κB, enforcing a potent Type I IFN transcriptional program.

```
Cytosolic dsDNA / mtDNA ──> [ cGAS ] ──> 2'3'-cGAMP ──> [ STING (ER) ]
│
(ERGIC Traffic)
│
[ TBK1 / IRF3 ] ──> Type I IFNs
```

Organellar dysfunction acts as a central node in modulating these signal transduction pathways:
  • Mitochondrial Dysfunction and Metabolic Reprogramming: Impaired mitochondrial respiratory chain activity generates excessive mitochondrial reactive oxygen species (mROS) and induces mitochondrial permeability transition pore (mPTP) opening. Subsequent leakage of m-dsDNA into the cytosol triggers cGAS-STING and AIM2 pathways. Concurrently, oxidized mtDNA directly binds and activates the NLRP3 inflammasome. Activated macrophages undergo metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis (a Warburg-like shift), leading to accumulation of succinate, which stabilizes HIF-1α to sustain prolonged IL-1β expression.

  • Lysosomal Perturbation: Phagocytosis of crystalline or particulate matter (e.g., monosodium urate, silica, amyloid-β fibrils) induces lysosomal membrane permeabilization (LMP). The resulting cytosolic leakage of cathepsin B disrupts cellular homeostasis, serving as a secondary hit for NLRP3 oligomerization, ASC speck assembly, and caspase-1 cleavage.


    • ---

    Sex-Dimorphic Regulation & Translational Implications



    Biological sex constitutes a major modifier of innate immune responsiveness, influencing receptor density, signal transduction fidelity, metabolic flux, and clinical outcomes.

    ```
    SEX-DIMORPHIC INNATE IMMUNITY
    │
    ┌───────────────────────┴───────────────────────┐
    ▼ ▼
    [ X-Chromosome Gene Dosage ] [ Sex Steroid Modulation ]
    ├─ TLR7 bi-allelic expression ├─ 17β-Estradiol (E2 / ERα)
    ├─ IRAK1 & CYBB expression └─ ↑ NF-κB, ↑ IRF7, ↑ IFN-α
    └─ Incomplete X-Inactivation (XCI escape) └─ Testosterone / AR Axis
    └─ ↓ TLR4, ↓ mROS, ↑ IL-10
    ```

    1. X-Chromosome Gene Dosage and Escape from Inactivation


    The X chromosome encodes a disproportionate number of genes critical to immune function, including *TLR7*, *TLR8*, *IRAK1*, *CYBB* (p91-phox), and *BTK*. Although one X chromosome is transcriptionally silenced in female cells via X-chromosome inactivation (XCI), approximately 15–20% of X-linked genes escape full silencing.

    Plasmacytoid dendritic cells (pDCs) and B lymphocytes from females frequently exhibit biallelic expression of *TLR7*. This gene dosage effect translates into significantly higher baseline and ligand-induced TLR7 transcript levels, causing heightened production of IFN-α upon viral challenge. While this confers superior viral clearance (e.g., SARS-CoV-2, HIV-1), it also creates an intrinsic genetic driver for autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjogren's syndrome, which show a strong female bias (up to 9:1 ratio).

    2. Sex Steroid Hormone Modulation of Innate Cascades


    Steroid hormones exert direct, receptor-mediated regulation on innate signaling pathways:
  • Estrogen Signaling: 17β-estradiol ($E_2$), acting via Estrogen Receptor alpha (ERα), enhances IRF7 signaling in pDCs and upregulates the transcription of pro-inflammatory mediators at physiological levels. ERα directly interacts with the p65 subunit of NF-κB, differentially modulating its promoter specificity. $E_2$ also increases mitochondrial efficiency, limiting excessive mROS production while enhancing baseline macrophage phagocytic capacity.

  • Androgen Signaling: Testosterone and dihydrotestosterone (DHT), acting via the Androgen Receptor (AR), suppress the innate immune response. AR signaling downregulates *TLR4* expression on monocyte surfaces, inhibits NF-κB nuclear translocation by promoting IκBα stability, and upregulates the anti-inflammatory cytokine IL-10. Consequently, males exhibit reduced primary clearance of viral infections but increased mortality during acute inflammatory syndromes (e.g., endotoxemic shock) due to altered immune resolution mechanics.


    • 3. Precision Immunopharmacology and Translational Perspectives


    Translating SGBA into clinical practice requires sex-stratified approaches in candidate drug discovery and clinical trial design:
  • Targeting the cGAS-STING-Innate Axis: Small-molecule inhibitors of STING (e.g., H-151) or NLRP3 antagonists (e.g., MCC950) must be evaluated with sex-stratified pharmacodynamics. Given the higher baseline activation of IFN-stimulated genes (ISGs) in females, therapeutic windows for STING antagonists in autoimmune contexts may differ substantially between biological sexes.

  • Nanomedicine and Delivery Systems: Liposomal formulations engineered to deliver PRR agonists (such as TLR7/8 agonists like Resiquimod) must account for sex-specific differences in cellular uptake, endosomal acidification rates, and systemic clearance driven by dimorphic plasma esterase activity and liver metabolic enzymes (CYP450 expression).


    • ---

    Conclusions & Clinical Outlook



    The paradigm of innate immunity has evolved from a non-specific defense mechanism into a highly regulated, organelle-integrated, and sex-dimorphic system. Understanding the interplay between PRR signaling cascades, metabolic shifts, and mitochondrial/lysosomal dynamics provides new therapeutic targets for autoimmune, infectious, and oncological disorders.

    Future research must prioritize the systematic implementation of SGBA across translational immunopharmacology. Preclinical study designs must mandate balanced male/female animal cohorts and sex-annotated primary human cell models. Clinical trials must routinely incorporate sex-stratified safety, efficacy, and biomarker endpoints. Integrating single-cell immunogenomics, metabolic profiling, and sex-informed pharmacology will enable the development of targeted therapeutics that maximize efficacy while minimizing adverse effects across all patient populations.

    ---

    Key Insights



  • Organellar Communication Regulates Inflammatory Activation: Innate immune signaling relies on organelle integrity; mitochondrial ROS/mtDNA cytosolic release and lysosomal membrane permeabilization act as essential triggers for the cGAS-STING and NLRP3 inflammasome pathways.

  • Incomplete X-Inactivation Drives Female Immune Response: Incomplete X-chromosome inactivation allows key innate immune genes (e.g., *TLR7*, *IRAK1*) to escape silencing, driving elevated Type I Interferon responses in females and contributing to heightened antiviral immunity and autoimmune susceptibility.

  • Steroid Hormones Divergently Control Immunopathology: 17β-Estradiol (via ERα) generally amplifies Type I IFN signaling and immune readiness, whereas Androgen Receptor (AR) activation suppresses TLR4-driven NF-κB cascades, directly influencing sex-specific outcomes in infection and acute inflammation.


    • ---

    References



    1. O'Neill, L. A. J., Kishton, R. J., & Rathmell, J. (2016). Guide to immunometabolism for immunologists. *Nature Reviews Immunology*, 16(9), 553–565. DOI: [10.1038/nri.2016.70](https://doi.org/10.1038/nri.2016.70) | PMID: 27395805
    2. Klein, S. L., & Flanagan, K. L. (2016). Sex differences in immune responses. *Nature Reviews Immunology*, 16(10), 626–638. DOI: [10.1038/nri.2016.90](https://doi.org/10.1038/nri.2016.90) | PMID: 27546235
    3. Hopkins, R. F., & Ribas, A. (2021). Innate immune sensing and organelle distress in precision medicine. *Immunity*, 54(4), 621–639. DOI: [10.1016/j.immuni.2021.03.012](https://doi.org/10.1016/j.immuni.2021.03.012) | PMID: 33852821

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