Chronic Inflammation in Immune Aging: Role of Pattern Recognition Receptor Crosstalk with the Telomere Complex?

Abstract

Age-related decline in immunity is characterized by stem cell exhaustion, telomere shortening, and disruption of cell-to-cell communication, leading to increased patient risk of disease. Recent data have demonstrated that chronic inflammation exerts a strong influence on immune aging and is closely correlated with telomere length in a range of major pathologies. The current review discusses the impact of inflammation on immune aging, the likely molecular mediators of this process, and the various disease states that have been linked with immunosenescence. Emerging findings implicate NF-κB, the major driver of inflammatory signaling, in several processes that regulate telomere maintenance and/or telomerase activity. While prolonged triggering of pattern recognition receptors is now known to promote immunosenescence, it remains unclear how this process is linked with the telomere complex or telomerase activity. Indeed, enzymatic control of telomere length has been studied for many decades, but alternative roles of telomerase and potential influences on inflammatory responses are only now beginning to emerge. Crosstalk between these pathways may prove to be a key molecular mechanism of immunosenescence. Understanding how components of immune aging interact and modify host protection against pathogens and tumors will be essential for the design of new vaccines and therapies for a wide range of clinical scenarios.

Keywords: NF-κB; inflammaging; myelopoiesis; pattern recognition receptor signaling; telomere shortening; toll-like receptor signaling.

Figure 1

Telomere length and telomerase activity during inflammation. Overview of the major cellular processes linking the telomere complex with inflammatory signaling and immunosenescence. Transcription factor NF-κB plays a crucial role in most inflammatory processes but also interacts with telomere control machinery and putative non-telomeric functions of the telomerase enzyme. (A) Low-grade inflammation in nfkb1^−/− mice causes increased ROS production and results in telomere dysfunction in mouse hepatocytes and intestinal crypt stem cells (29). (B) One of the reported non-telomeric functions of human telomerase enzyme (TERT) is the ability to inhibit endogenous ROS production and regulate oxidative stress in cancer cell lines (155). (C) Mice lacking telomerase RNA component (TERC) succumb to LPS administration due to endotoxin shock arising from chromosome instability in splenocytes and macrophages (136). (D) Signaling downstream of inflammatory cytokines such as IFN-α plays an important role in downregulation of TERT activity in hematopoietic cells (159). (E) In contrast, interleukin (IL)-6 and tumor necrosis factor (TNF)-α reportedly upregulate TERT transcription and telomerase activity through activation and binding of NF-κB in macrophages (47) or NF-κB, STAT1, and STAT3 interactions with the TERT promoter in splenocytes and cancer cells (16, 158). (F) Ghosh et al. have also described the ability of TERT to directly regulate NF-κB-dependent gene expression in primary bone marrow blasts from leukemic patients (160).