Maladaptive trained immunity and clonal hematopoiesis as potential mechanistic links between periodontitis and inflammatory comorbidities

Abstract

Periodontitis is bidirectionally associated with systemic inflammatory disorders. The prevalence and severity of this oral disease and linked comorbidities increases with aging. Here, we review two newly emerged concepts, trained innate immunity (TII) and clonal hematopoiesis of indeterminate potential (CHIP), which together support a potential hypothesis on how periodontitis affects and is affected by comorbidities and why the susceptibility to periodontitis and comorbidities increases with aging. Given that chronic diseases are largely triggered by the action of inflammatory immune cells, modulation of their bone marrow precursors, the hematopoietic stem and progenitor cells (HSPCs), may affect multiple disorders that emerge as comorbidities. Such alterations in HSPCs can be mediated by TII and/or CHIP, two non-mutually exclusive processes sharing a bias for enhanced myelopoiesis and production of innate immune cells with heightened proinflammatory potential. TII is a state of elevated immune responsiveness based on innate immune (epigenetic) memory. Systemic inflammation can initiate TII in the bone marrow via sustained rewiring of HSPCs, which thereby display a skewing toward the myeloid lineage, resulting in generation of hyper-reactive or "trained" myeloid cells. CHIP arises from aging-related somatic mutations in HSPCs, which confer a survival and proliferation advantage to the mutant HSPCs and give rise to an outsized fraction of hyper-inflammatory mutant myeloid cells in the circulation and tissues. This review discusses emerging evidence that supports the notion that TII and CHIP may underlie a causal and age-related association between periodontitis and comorbidities. A holistic mechanistic understanding of the periodontitis-systemic disease connection may offer novel diagnostic and therapeutic targets for treating inflammatory comorbidities.

Keywords: aging; clonal hematopoiesis; comorbidities; hematopoietic stem cells; periodontitis; trained immunity.

Figure 1.. Periodontitis-related systemic inflammation and inflammatory modulation of bone marrow progenitor cells.

In periodontitis, bacteria from the tooth-associated dysbiotic biofilm may translocate through the ulcerated periodontal pockets into the blood circulation, resulting in bacteremias and systemic inflammation. Systemic inflammation, in turn, may cause inflammatory modulation of hematopoietic stem and progenitor cells promoting increased myelopoiesis. HSC, hematopoietic stem cell; MPP, multipotent progenitor; GMP, granulocyte-monocyte progenitor.

Figure 2.. A vicious feed-forward loop linking periodontitis to inflammation-adapted HSPCs in the context of trained immunity and clonal hematopoiesis.

The ability of bone marrow HSPCs to not only sense but also adapt to pro-inflammatory stimuli underlies the induction of trained immunity, leading to sustained enhanced myelopoiesis and generation of myeloid cells with heightened immune preparedness and responsiveness. Clonal hematopoiesis of indeterminate potential (CHIP) results from age-related somatic mutations in HSPCs that endow the mutant HSPCs with a proliferative advantage, especially under inflammatory conditions, thereby generating an outsized fraction of hyper-inflammatory mutant myeloid cells. Periodontitis-associated systemic inflammation may thus contribute to induction of trained innate immunity and shaping of an inflammatory bone marrow microenvironment conducive for the selective expansion of CHIP-mutant HSC clones. The generated hyper-responsive or hyper-inflammatory myeloid cells are recruited to sites of infection and inflammation and can thus exacerbate periodontitis, which in turn can exert increased inflammatory influence on the bone marrow. Thus, a self-sustained feed-forward loop may be generated between inflammation-adapted HSPCs and periodontitis that could contribute to the chronicity of this oral disorder.

Figure 3.. Trained innate immunity.

Trained innate immunity represents non-specific immune memory which can be induced, independent of adaptive immunity, upon an earlier microbial challenge and can be recalled at later time points in response to a new challenge that is not necessarily the same with the primary one. The induction of the memory or trained phenotype can be initiated in the bone marrow via long-lived metabolic, epigenetic, and transcriptional adaptations in hematopoietic stem and progenitor cells, which in turn give rise to trained mature myeloid progeny with augmented immune and inflammatory responsiveness.

Figure 4.. CHIP may potentially affect multiple inflammatory disorders.

With advancing age, HSPCs progressively acquire somatic mutations that confer increased self-renewal capacity and myeloid differentiation bias, giving rise to mutant myeloid progeny with enhanced pro-inflammatory potential, as compared to their counterparts from normal HSPC clones. This condition, which - in the absence of apparent hematological malignancy - is designated clonal hematopoiesis of indeterminate potential (CHIP) has been epidemiologically and experimentally linked with atherosclerotic cardiovascular disease. However, the generation and release of hyper-inflammatory myeloid cells in the context of CHIP may contribute to inflamm-aging and elevate systemic inflammation, which in turn could contribute to the pathogenesis of additional inflammatory pathologies, such as periodontitis and rheumatoid arthritis.

Figure 5.. Western diet leads to NLRP3 Inflammasome activation and induction of maladaptive trained immunity.

In mice, western-type diet, in great part through oxidized LDL, induces activation of the NLRP3 inflammasome and caspase 1-dependent secretion of IL-1β, which induces expansion and epigenetic reprogramming of bone marrow progenitor cells (including GMPs), which in turn drive trained myelopoiesis (increased numbers of myeloid cells with enhanced immune responsiveness) that can perpetuate systemic inflammation. These maladaptive alterations persist even after the mice are switched back to a healthy diet.