Stroke-induced trained immunity spells bad news for the heart

Inflammatory memory in the bone marrow has been proposed as a common mechanistic basis driving the emergence of comorbidities. In a recent Cell paper, Simats et al. show that stroke-induced inflammation causes persistent inflammatory memory in hematopoietic progenitors that give rise to hyper-inflammatory monocytes that infiltrate the heart and promote cardiac dysfunction.

The new concept that innate immune cells can also build memory of earlier infectious or inflammatory encounters — albeit of different nature and duration from classical immunological memory of adaptive immunity — has recently changed the way scientists and clinicians can explain chronic inflammation and the emergence of inflammatory multimorbidity. Innate immune memory is imprinted in the epigenome and, although reversible in principle, can have long-lasting effects. Indeed, epigenetic modifications in inflammatory genes, enhancing their accessibility for transcription, form the basis of trained immunity (TRIM), i.e., the augmented immune response to a future challenge that is not necessarily the same as the memory-inducing one.¹ Although TRIM can augment host resistance to future insults such as infections and cancer,¹ it may also enhance detrimental inflammatory responses that mediate immune-mediated diseases.² Of particular importance in this regard is TRIM that is initiated in long-lived hematopoietic progenitors in the bone marrow, termed central TRIM to distinguish it from peripheral TRIM that can be induced in mature innate immune cells in the periphery.¹ This is because central TRIM mediated by hematopoietic stem and progenitor cells (HSPCs) can sustainably provide hyper-responsive myeloid cells, which are key players in the pathogenesis of different chronic inflammatory disorders.¹

The concept that central TRIM may constitute a common mechanistic basis for inflammatory comorbidities (hence ‘maladaptive’ TRIM) was first shown in the setting of the periodontitis-arthritis axis, two inflammatory bone loss disorders that often coexist in patients.² In that study, naïve mice were transplanted with whole bone marrow cells, or with isolated hematopoietic stem cells (HSCs), from donor mice with past periodontitis (i.e., the donors were treated to resolve disease and were healthy at the time their bone marrow was harvested). Twelve weeks post transplantation, the naïve recipients displayed an elevated myelopoiesis response and increased tissue destruction when they underwent experimental periodontitis or arthritis. Similarly, transplantation of bone marrow from arthritis-subjected mice transmitted the maladaptive trained phenotype to naïve recipients, which thus became more susceptible to experimental periodontitis or arthritis.²

In a recent study in mice, Simats et al.³ implicated maladaptive central TRIM as a key mediating connection between acute brain ischemia and cardiac dysfunction (Fig. 1). Specifically, after they subjected mice to transient intraluminal occlusion of the middle cerebral artery to model ischemic stroke, they also found out that the mice developed long-lasting innate immune memory in the bone marrow HSPCs as well as cardiac fibrosis and dysfunction when examined 1 or 3 months after the stroke. This post-stroke trained phenotype could be transmitted via bone marrow transplantation to naïve mice, which exhibited cardiac dysfunction 1 month post transplantation.³ Mechanistically, stroke-trained HSPCs gave rise to hyper-inflammatory monocytes that were recruited in high numbers to the heart, wherein they enhanced inflammation and fibrosis. The latter was characterized by enhanced deposition of type I collagen in the extracellular matrix and resulted from the enhanced ability of the recruited trained monocytes to activate fibroblasts and release matrix metalloproteinase 9 (MMP9), which can activate latent TGFβ1, a profibrotic cytokine.³

Ischemic stroke leads to IL-1β inflammation that induces persistent epigenetic alterations associated with innate immune training of HSPCs in the bone marrow. Monocytes generated downstream of granulocyte-monocyte progenitors (GMPs) are trained and infiltrate the heart where they contribute to increased inflammation and fibrosis (by inducing fibroblast activation and MMP9 release), ultimately causing cardiac dysfunction. Figure created with BioRender.com.

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The generation of central TRIM in this model was mediated by early post-stroke IL-1β production. Indeed, antibody-mediated neutralization of IL-1β during the acute phase inhibited most of the stroke-induced epigenetic changes associated with the training of HSPCs and their progeny monocytes and consequently the downstream sequela (increased myelopoiesis and cardiac tissue infiltration with inflammatory monocytes, MMP9 upregulation, fibrosis), leading to post-stroke cardiac dysfunction.³ Interestingly, the aforementioned periodontitis-induced maladaptive central TRIM was also dependent upon IL-1 signaling since it failed in mice with HSPC-specific deletion of the IL-1 receptor.² Similarly, IL-1 is critical for induction of trained myelopoiesis (i.e., increased production of hyper-responsive myeloid cells by trained HSPCs) in the context of atherosclerosis.⁴ These findings might suggest that the protective effects of IL-1β neutralization observed in the CANTOS trial⁵ — wherein treatment of patients resulted in reduced incidence of major cardiovascular events as well as of arthritis, gout and osteoarthritis — could, in part, result from inhibition of central TRIM. Because inhibition of IL-1 signaling entails increased risk of infections, the authors tried also an alternative therapeutic approach targeting the outcome rather than the initiation of maladaptive TRIM. Specifically, they used cenicriviroc (CVC) — an antagonist with dual blocking action for C-C chemokine receptor types 2 and 5 (CCR2/5) — and were successful in blocking the migration of hyper-inflammatory monocytes to the heart and thereby preventing the development of post-stroke cardiac dysfunction. Importantly, application of CVC in humans was shown to be safe.⁶

Clinical and experimental studies show that acute and persistent inflammatory responses follow after a stroke and can lead to post-stroke morbidity affecting the prognosis of stroke patients.⁷ In this context, the authors associated stroke with cardiac fibrosis and diastolic dysfunction although confirmation in a prospective study would strengthen the notion for a causal association. Future studies may also aim to obtain evidence that post-stroke inflammation in humans can lead to trained myelopoiesis in the bone marrow, thereby lending further support to the notion that trained myelopoiesis links post-stroke inflammation to chronic cardiac dysfunction in humans. Patients with chronic inflammatory disorders, including periodontitis and rheumatoid arthritis, have elevated systemic inflammation and increased risk of cardiovascular disease.⁸ In these patients there is also evidence for the presence of persistent innate immune memory in peripheral neutrophils and monocytes, possibly resulting from central TRIM considering the limited lifetime of circulating myeloid cells and particularly neutrophils.⁸ It is therefore conceivable that systemic inflammation induced by acute brain ischemia may induce inflammatory memory in the bone marrow and render stroke patients susceptible to not only cardiac dysfunction but also other inflammatory disorders.

The study by Simats et al. as well as another recent one, which implicated maladaptive trained myelopoiesis in the connection between heart failure and cardiac fibrosis and dysfunction in mice,⁹ provide strong support to the emerging concept that systemic inflammation, deriving from either acute (e.g., ischemic stroke and acute heart failure) or chronic conditions (e.g., periodontitis, arthritis, diabetes, obesity), may lead to persistent inflammatory memory that can trigger further inflammatory processes that promote the emergence of comorbid pathologies.^2,3,9,10 The identification of common initiating pathways that generate maladaptive TRIM has the potential to lead to holistic approaches to treat or mitigate inflammatory comorbidities.