DNA Damage-Induced Inflammatory Microenvironment and Adult Stem Cell Response

Abstract

Adult stem cells ensure tissue homeostasis and regeneration after injury. Due to their longevity and functional requirements, throughout their life stem cells are subject to a significant amount of DNA damage. Genotoxic stress has recently been shown to trigger a cascade of cell- and non-cell autonomous inflammatory signaling pathways, leading to the release of pro-inflammatory factors and an increase in the amount of infiltrating immune cells. In this review, we discuss recent evidence of how DNA damage by affecting the microenvironment of stem cells present in adult tissues and neoplasms can affect their maintenance and long-term function. We first focus on the importance of self-DNA sensing in immunity activation, inflammation and secretion of pro-inflammatory factors mediated by activation of the cGAS-STING pathway, the ZBP1 pathogen sensor, the AIM2 and NLRP3 inflammasomes. Alongside cytosolic DNA, the emerging roles of cytosolic double-stranded RNA and mitochondrial DNA are discussed. The DNA damage response can also initiate mechanisms to limit division of damaged stem/progenitor cells by inducing a permanent state of cell cycle arrest, known as senescence. Persistent DNA damage triggers senescent cells to secrete senescence-associated secretory phenotype (SASP) factors, which can act as strong immune modulators. Altogether these DNA damage-mediated immunomodulatory responses have been shown to affect the homeostasis of tissue-specific stem cells leading to degenerative conditions. Conversely, the release of specific cytokines can also positively impact tissue-specific stem cell plasticity and regeneration in addition to enhancing the activity of cancer stem cells thereby driving tumor progression. Further mechanistic understanding of the DNA damage-induced immunomodulatory response on the stem cell microenvironment might shed light on age-related diseases and cancer, and potentially inform novel treatment strategies.

Keywords: DNA damage; cancer; immune response; inflammation; microenvironment; stem cells.

FIGURE 1

Changes in the stem cell microenvironment upon DNA damage. Simplified schematic representation of the tissue microenvironment during homeostasis (Left) and inflammation (Right). DNA damage can impair tissue homeostasis by promoting senescence, cytokine and SASP release. Cytokines and chemokines present in the microenvironment can lead to recruitment of immune cells and activation of tissue-resident macrophages.

FIGURE 2

Overview of the main pathways responsible for cytosolic nucleic acid recognition. DNA damage can trigger the formation of micronuclei and the release of double stranded DNA (dsDNA) into the cytoplasm. Mitochondria can also be a source of cytoplasmic DNA and RNA upon genomic stress. AIM2 and NLRP3 are part of two distinct inflammasome complexes, responsible for the bioactivation of Caspase-1 (CASP1); activated CASP1 in turn cleaves and promotes the activation of IL-1β and IL-18, which leave the cell upon inflammasome-mediated pyroptosis. cGAS is the main protein responsible for cytoplasmic dsDNA recognition; upon dsDNA binding cGAS promotes the formation of cGAMP, which binds and activates STING; STING in turn promotes the activation of IRF3 and NF-kB transcription factors responsible for the expression of IFN1 and various cytokines. IFN1 is then able to leave the cell and interact with its receptor; this interaction leads to STAT1, STAT2 and IRF9 complex (ISGF3) translocation into the nucleus and transcription of interferon stimulated genes (ISGs). ISGF3 activation can also lead to expression of ancestor endogenous retroviruses (ERVs) in form of double stranded RNA (dsRNA). Cytoplasmic dsRNA is recognized by RIG-1 and MDA5, which trigger the activation of IRF3. On the other hand, Dicer can sense and cleave both cytoplasmic and nucleic dsRNA. IFI16 is an ISG able to recognize dsDNA and activate STING. ZBP1 promotes IRF3 and NLRP3 activation, and Caspase-8 (CASP8)-mediated necroptosis upon recognition of Z forms of dsDNA.

FIGURE 3

Infiltration of immune cells into the normal stem cell and cancer stem cell niche. DNA damage can trigger the release of various cytokines and chemokines into the microenvironment (1); these can lead to migration and recruitment of macrophages (2) that exit the circulation and infiltrate into the tissue (3). The inflammatory microenvironment is then able to trigger the polarization of these macrophages (4) into M1 or M2 subtypes. Tissue-resident macrophages are normally present into the stem cell microenvironment, and they are important for the maintenance of the stem cell niche (5). The tumor microenvironment can lead to recruitment of various immune cells (6); tumor associated macrophages (TAM) can secrete inflammatory cytokines important for tumor growth and expansion (7); natural killer (NK) cells can potentially recognize and eliminate cancer stem cells (CSC) upon infiltration (8). T-cells can infiltrate into the normal stem cell niche (9) influencing stem cell proliferation and homeostasis; some types of stem cells are able to secrete molecules able to inhibit activation and differentiation of infiltrated T-cells (10).