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Inflammation and DNA damage: cause, effect or both

Nature Reviews Rheumatology volume 19, pages 200–211 (2023)Cite this article

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Abstract

Inflammation is a biological response involving immune cells, blood vessels and mediators induced by endogenous and exogenous stimuli, such as pathogens, damaged cells or chemicals. Unresolved (chronic) inflammation is characterized by the secretion of cytokines that maintain inflammation and redox stress. Mitochondrial or nuclear redox imbalance induces DNA damage, which triggers the DNA damage response (DDR) that is orchestrated by ATM and ATR kinases, which modify gene expression and metabolism and, eventually, establish the senescent phenotype. DDR-mediated senescence is induced by the signalling proteins p53, p16 and p21, which arrest the cell cycle in G1 or G2 and promote cytokine secretion, producing the senescence-associated secretory phenotype. Senescence and inflammation phenotypes are intimately associated, but highly heterogeneous because they vary according to the cell type that is involved. The vicious cycle of inflammation, DNA damage and DDR-mediated senescence, along with the constitutive activation of the immune system, is the core of an evolutionarily conserved circuitry, which arrests the cell cycle to reduce the accumulation of mutations generated by DNA replication during redox stress caused by infection or inflammation. Evidence suggests that specific organ dysfunctions in apparently unrelated diseases of autoimmune, rheumatic, degenerative and vascular origins are caused by inflammation resulting from DNA damage-induced senescence.

Key points

  • Persistent DNA damage of mitochondrial or nuclear DNA and the DNA damage response represent the common features of every type of inflammation, whether systemic or organ specific.

  • Senescence, characterized by permanent cell-cycle arrest and the secretion of inflammatory cytokines, is the main response to and consequence of DNA damage.

  • The heterogeneity of the organ or tissue inflammation and senescent phenotypes in response to DNA damage is the result of the concomitant presence of several cell-type-specific phenotypes in mitotic and postmitotic cells.

  • Persistent DNA damage maintained by senescence induces loss or change of epigenetic memory (DNA methylation and chromatin configuration), leading to reactivation of silenced genes, and further diffuse inflammation and DNA damage response.

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Fig. 1: Main actors linking DNA damage to inflammation.
Fig. 2: DNA damage and DNA damage response reprogramme energy metabolism.
Fig. 3: cGAS–STING signalling and DNA damage repair.
Fig. 4: Positive feedback between inflammation and persistent DNA damage in senescence.

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Acknowledgements

A. Pezone is supported by the PON R&I 2014-2020 [E65F21002850007], E.V.A. is supported by the POR Campania FESR 2014-2020 “SATIN” grant, and A.G. is supported by Fondazione di Medicina Molecolare e Terapia Cellulare (Ancona-Italy).

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Authors and Affiliations

  1. Dipartimento di Biologia, Università Federico II, Napoli, Italy

    Antonio Pezone

  2. Dipartimento di Scienze Cliniche e Molecolari, DISCLIMO, Università Politecnica delle Marche, Ancona, Italy

    Fabiola Olivieri, Maria Vittoria Napoli & Antonio Procopio

  3. Clinica di Medicina di Laboratorio e di Precisione, IRCCS INRCA, Ancona, Italy

    Fabiola Olivieri & Antonio Procopio

  4. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R., Università Federico II, Napoli, Italy

    Enrico Vittorio Avvedimento

  5. Fondazione di Medicina Molecolare e Terapia Cellulare, Università Politecnica delle Marche, Ancona, Italy

    Armando Gabrielli

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M.V.N. researched data for the article. A. Pezone, F.O., A. Procopio, E.V.A. and A.G. contributed substantially to discussion of the content. A. Pezone, M.V.N., A. Procopio, E.V.A. and A.G. wrote the article. M.V.N. reviewed and edited the manuscript before submission.

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Glossary

Endocrinosenescence

Endocrine dysfunction that occurs with age.

Epigenetic modification

Heritable chemical or physical change in chromatin that is not a change in DNA sequence.

Immunosenescence

Immune dysfunction that occurs with age.

Meta-inflammation

A chronic state of inflammation mediated by macrophages located within the colon, liver, muscle and adipose tissue.

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Pezone, A., Olivieri, F., Napoli, M.V. et al. Inflammation and DNA damage: cause, effect or both. Nat Rev Rheumatol 19, 200–211 (2023). https://doi.org/10.1038/s41584-022-00905-1

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