cGAS-STING pathway as a potential trigger of immunosenescence and inflammaging

Carine Raquel Richter Schmitz; Rafael Moura Maurmann; Fatima T C R Guma; Moisés Evandro Bauer; Florencia Maria Barbé-Tuana

doi:10.3389/fimmu.2023.1132653

cGAS-STING pathway as a potential trigger of immunosenescence and inflammaging

Front Immunol. 2023 Feb 28:14:1132653. doi: 10.3389/fimmu.2023.1132653. eCollection 2023.

Authors

Carine Raquel Richter Schmitz^{1

2}, Rafael Moura Maurmann^{1

3}, Fatima T C R Guma², Moisés Evandro Bauer^{1

3

4

5}, Florencia Maria Barbé-Tuana^{1

3

6

7}

Affiliations

¹ Laboratório de Imunobiologia, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
² Programa de Pós-Graduação em Ciência Biológicas - Bioquímica, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
³ Programa de Pós-Graduação em Biologia Celular e Molecular, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
⁴ Instituto Nacional de Ciência e Tecnologia - Neuroimunomodulação (INCT-NIM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brasília, Brazil.
⁵ Programa de Pós-Graduação em Gerontologia Biomédica, Escola de Medicina, Pontifícia Universidade do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
⁶ Programa de Pós-Graduação em Biologia Celular e Molecular da Escola de Ciências da Saúde da Vida, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
⁷ Programa de Pós-Graduação em Pediatria e Saúde da Criança da Escola de Medicina, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.

Abstract

Aging is associated with an increased incidence of autoimmune diseases, despite the progressive decline of immune responses (immunosenescence). This apparent paradox can be explained by the age-related chronic low-grade systemic inflammation (inflammaging) and progressive dysregulation of innate signaling. During cellular aging, there is an accumulation of damaged DNA in the cell's cytoplasm, which serves as ubiquitous danger-associated molecule, promptly recognized by DNA sensors. For instance, the free cytoplasmic DNA can be recognized, by DNA-sensing molecules like cGAS-STING (cyclic GMP-AMP synthase linked to a stimulator of interferon genes), triggering transcriptional factors involved in the secretion of pro-inflammatory mediators. However, the contribution of this pathway to the aging immune system remains largely unknown. Here, we highlight recent advances in understanding the biology of the cGAS-STING pathway, its influence on the senescence-associated secretory phenotype (SASP), and its modulation of the immune system during sterile inflammation. We propose that this important stress sensor of DNA damage is also a trigger of immunosenescence and inflammaging.

Keywords: NF-κB; SASP; aging; cGAS; immunosenescence; inflammaging; senescence.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Cellular Senescence / genetics
DNA / metabolism
Humans
Immunosenescence*
Inflammation
Nucleotidyltransferases / metabolism

Substances

DNA
Nucleotidyltransferases

Grants and funding

This article was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES). CS and RM received a scholarship from CAPES. FG and MB are senior investigators from CNPq.