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Review
. 2022 May 23;12(5):737.
doi: 10.3390/biom12050737.

Innate Immunity: A Balance between Disease and Adaption to Stress

Irene Faenza  1 , William L Blalock  2   3
Affiliations
Review

Innate Immunity: A Balance between Disease and Adaption to Stress

Irene Faenza et al. Biomolecules. .

Abstract

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation itself acts as a potent promoter of injury and disease. Additionally, results from studies over the last 25 years point to chronic inflammation and innate immune signaling as a critical link between stress (exogenous and endogenous) and adaptation. This brief review looks to highlight the role of the innate immune response in disease pathology, and recent findings indicating the innate immune response to chronic stresses as an influence in driving adaptation.

Keywords: Fanconi anemia; adaption; autoinflammation; cancer; inflammation; innate immunity; neuro-muscular degeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Innate Immune Signaling. The major signal transduction pathways mediated by extracellular and intracellular Pattern Recognition Receptors (PRRs) of both Pathogen-Associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs) are presented. (a) Extracellular pathogens, stressors, and products from damaged cells can result in the stimulation of the receptor for advanced glycation end products (RAGE; high mobility group box (HMGB)-1, advanced glycation end products (AGE)), C-type lectin (C-TL; glycoproducts of bacteria, fungi) or Toll-like receptors (TLR; nucleic acids, LPS, glycoproteins), primarily resulting in the activation of nuclear factor-κB (NF-κB) through signaling mediated by AKT and/or PKR. AKT stimulates survival, while PKR phosphorylates eukaryotic initiation factor 2α (eIF2α) and p53, inhibiting general translation and promoting p53 stability, respectively. Additionally, PKR results in both the phosphorylation and degradation of inhibitor κB (IκB) and the phosphorylation of p65 NF-κB, promoting the translocation of p65 NF-κB to the nucleus and the stimulation of NFκB-dependent transcripts, including cytotoxic cytokines and type I interferon. Activation of the intracellualar PRRs (RIG-I, MDA5, or cGAS) promote the phosphorylation and activation of interferon response factors (IRF)-3 and -7. In conjunction with p65 NF-κB, IRF3/7 stimulates the synthesis of type I interferon, which is secreted, thereby having both paracrine and autocrine effects. The associated signaling can promote cell death as well as the recruitment of immune cells to the site of damage/stress. AKT-mediated suppression of GSK3 promotes β-catenin (β-cat) translocation to the nucleus and the synthesis of IRF3. In many autoinflammatory/degenerative diseases, GSK3 remains active and interferon signaling is defective. (b) Under chronic stress conditions (environmental factors, DNA repair defects (FANC)), prolonged activation of the PRRs and interferon-inducible kinase PKR leads to phosphorylation and inactivation of the DNA repair kinase, ATM, and an enhancement in the rate of mutagenesis. In addition, a number of interferon-inducible proteins, which act as both epigenetic modifiers and DNA repair proteins, associate with sites of DNA strand breaks, potentially regulating the mutation incorporation rate.
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Grants and funding

This work was funded by Ricerca fondamentale orientata (RFO), University of Bologna, (to IF).

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