By Stefanija Kinzy (BS 2024, MD candidate 2030)
There is a complex interplay between the cell cycle and immune systems. Inflammation can impact cell cycle progression in many ways: from inflammatory cell death via cytokine shock to inflammation-induced increased cell proliferation.
Pattern Recognition Receptors (PRRs), like TLRs and RLRs, are the first line of intracellular defense against pathogenes. Toll-like receptor (TLR) activation results in pro-inflammatory cytokine release (Kawai and Akira 2009). RIG-I -like receptors (RLRs) interact with intracellular components of the JAK-STAT pathway, which leads to the expression of interferon-stimulated genes (ISGs), and the production of type I and type III interferons and inflammatory cytokines, strong antiviral response (Onomoto, Onoguchi, and Yoneyama 2021). Inflammatory cell death has been shown in studies relating to COVID-19, where treatment with the combination of TNF-α and IFN-γ led to synergistic mortality in mice, with markers correlating to lab abnormalities in patients with COVID-19 (Karki, Sharma, et al. 2021).
Cytokine shock, or the cytokine storm in severe cases, is caused by excessive cytokine release mediated by a positive feedback loop in which cytokine release causes inflammatory cell death, which induces pathogenic cytokine release through cell lysis, and results in potentially lethal tissue damage in response to pathogens, monogenic abnormalities, and some types of therapeutic intervention (Karki, Sharma et al. 2021). In cases of acute inflammation, there can be a kinetic barrier that separates DNA damage from cell proliferation, protecting against mutations (Kiraly, Gong, et al. 2015). Inflammation was found to induce DNA double-strand breaks that promoted cell proliferation which, when combined with alkylation damage, induced homologous recombination synergistically (Kiraly, Gong et al. 2015). This data indicates that inflammation-induced proliferation enhances the production of exposure-induced mutant cells, which may be a mechanism that drives cancer growth and recurrence (Kiraly, Gong et al. 2015).
This influence is not unidirectional, the cell cycle can also influence immune responses. Some cell cycle regulators, like cyclins, CDKs, and CKIs, are required elements in the accumulation of T and B cells in active immune responses, as they indirectly control lymphocyte activity in T cell activation and cyclin DC-CDK6 is required in thymocyte production (Laphanuwat and Jirawatnotai 2019). There is a positive correlation between T-cell production of effector cytokines on secondary exposure and the number of times that the cell has undergone the cell cycle (Bird, Brown, et al. 1998). In addition, sensitivity to interferon stimulation has been linked to feedback control through the cell-cycle stage, where only G1 and early S phases allow for USP18 upregulation upon interferon treatment (Mudla, Jiang, et al. 2020).