Old Dog New Tricks; Revisiting How Stroke Modulates the Systemic Immune Landscape

Abstract

Infections in the post-acute phase of cerebral ischaemia impede optimal recovery by exacerbating morbidity and mortality. Our review aims to reconcile the increased infection susceptibility of patients post-stroke by consolidating our understanding of compartmentalised alterations to systemic immunity. Mounting evidence has catalogued alterations to numerous immune cell populations but an understanding of the mechanisms of long-range communication between the immune system, nervous system and other organs beyond the involvement of autonomic signalling is lacking. By taking our cues from established and emerging concepts of neuro-immune interactions, immune-mediated inter-organ cross-talk, innate immune training and the role of microbiota-derived signals in central nervous system (CNS) function we will explore mechanisms of how cerebral ischaemia could shape systemic immune function. In this context, we will also discuss a key question: how are immune requirements critical for mediating repair of the ischaemic insult balanced by the need for anti-microbial immunity post-stroke, given that they are mediated by mutually exclusive immune networks? Our reformed understanding of the immune landscape post-stroke and novel mechanisms at play could guide targeted therapeutic interventions and initiate a step-change in the clinical management of these infectious complications post-stroke.

Keywords: cerebral ischaemia; innate immune training; neuroimmunology; post-stroke infection; systemic immunity.

Figure 1

The spectrum of systemic immune alterations post-stroke and the potential mechanisms exploited by stroke to mediate these long-range effects. Stroke, through its effects on autonomic and HPA axis activation, innate immune training, and microbial communities in the gut can gain access to various tissues to shape the systemic immune landscape, affecting cellular, and cytokine networks. Acting in synergy, these means of long-range communication modulate the frequency and functional responsiveness of a plethora of immune cells, tuning the quality of the immune response elicited in various tissues in response to CNS injury. CCL2, chemokine (C-C motif) ligand 2; CXCL1, chemokine (C-X-C motif) ligand 1; IFN-γ, interferon- γ; HPA, hypothalamic-pituitary-adrenal; IL, interleukin; iNKT cell, invariant natural killer T cell; NK cell, natural killer cell; SCFA, short chain fatty acids; SI, small intestine; TNF-α, tumour necrosis factor-α.