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The hidden damage of brain injury after intracranial haemorrhage.

Authors: Jessie W Ho1, Zaiba Shafik Dawood1, Hasan B Alam1
1Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Corresponding Author:
Hasan B. Alam, MD, FACS
Loyal and Edith Davis Professor of Surgery, and Professor of Cell & Developmental Biology Chair, Department of Surgery, Feinberg School of Medicine, Northwestern University Surgeon-in-Chief, Northwestern Memorial Hospital

Funding: None
Conflict of Interest: The authors declare no conflicts of interest
Data availability: N/A

This article highlights the close relation between the central nervous system and peripheral immune system, forming a neuroimmune axis that has clinical implications we are just beginning to understand. This article from the journal Science and Translational Medicine  couples both patient data and a mouse model of intracranial haemorrhage (ICH) to explore the influence of ICH on haematopoietic stem cells (HSC) and the subsequent impact of HSCs on the brain.

In the first experiment, bone marrow cells were harvested from skull flaps of patients requiring decompressive craniotomies for ICH and compared with cells from patients with unruptured aneurysms. In the second, ICH was induced in a mouse model by injection of autologous blood into brain parenchyma and subsequent harvest of femur bone marrow cells. Both the human and mouse data demonstrated increased myeloid progenitor cells and haematopoiesis with ICH. Adrenergic innervation through the β3 receptor on haematopoietic cells promotes production of Ly6Clow , a patrolling non-classical monocyte (NCM), in the bone marrow, which rapidly travels to the brain after ICH. Through transcriptomic analysis of the HSCs after ICH, Cdc42 (cell division cycle 42) was identified as an upregulated gene. Cdc42 was noted to be ablated in β3-adrenergic knockout mice, Adrb3-/-, linking the relationship of Cdc42 and adrenergic innervation. Treatment with a Cdc42 inhibitor led to decreased bone marrow proliferation, reduced Ly6Clow monocytes, and exacerbated brain injury. Given the role of the β3 receptor in proliferation and targeting of haematopoietic cells, mice were treated with a US Food and Drug Administration approved β3 receptor agonist, mirabegron. As expected, mirabegron treatment increased the Cdc42 activity in HSCs and increased Ly6Clow production and concentration in the brain. Most importantly mirabegron treatment reduced functional neurological deficits, perihaematomal oedema, and overall brain oedema after ICH.

This article demonstrates that brain injury leads to a cascade of mechanisms modulated by β3-adrenergic innervation in which an NCM population provides protective effects to the brain. Lastly, the authors tested a potential targeted therapy upregulating the pathway and demonstrated improvement in brain injury outcomes.

Brain injuries have unique mechanisms that differ from peripheral organ injury. In normal conditions, the brain is sheltered within the blood brain barrier (BBB); endothelial cells and the microvasculature tightly regulate the exchange of molecules, ions, and cells from the blood to the brain.2 When the brain is injured, in particular in traumatic brain injury (TBI), there is a combination of mechanical disruption and endothelial dysfunction leading to BBB permeability. Disruption of the BBB leads to the circulation of brain-derived damage associated molecular patterns (DAMPs) in the peripheral circulation.3 At the same time, the injured brain is exposed to the peripheral circulation, due to BBB disruption. The complex interplay and cross-talk between the injured brain and the distant organs is just beginning to be investigated.

Shi et al1 add to the body of literature evaluating the connection between brain injury and the immune system. Given the relatively broad potential aetiologies of ICH (e.g. trauma, aneurysm rupture, tumour, coagulopathy), this article is widely applicable and should stimulate future questions in understanding brain injury. Severe TBI has been associated with a systemic inflammatory response syndrome with downstream effects that can lead to multi-organ dysfunction (MOD). The systemic response provides notable clinical evidence for the interactions between the brain and periphery. In 2021, Yang et al evaluated the role of the Ly6clow NCM in the mechanisms of pulmonary oedema following TBI.4 Their group demonstrated that there is a significant increase in Ly6clow NCM in the lungs of mice after TBI. Upon depletion of NCMs, there was a decrease in pulmonary oedema suggesting that NCMs contribute to post-TBI lung injury. Taken together, these articles show that NCMs are stimulated in the bone marrow following TBI. Subsequently, their response plays a role in both local brain inflammation, as well as distant organ injury. Interestingly, while the Ly6clow NCM migration appears to improve brain injury,1 the increase of Ly6clow in the lungs was associated with worse outcomes. Given the interconnected nature of the immune system, these findings raise many more questions than answers. Among the many are: what the NCM response is in other organs, what downstream cell type do they effect, and how do the NCMs migrate to the distant organs?

In understanding the mechanisms and pathways driving the brain and peripheral cross-talk, we may begin to not only investigate therapies and diagnostics in brain injury, but also target the associated MOD. Currently, the treatment for brain injury is largely supportive, with no interventions that target the underlying mechanisms. These mechanisms provide promising avenues for future research and the potential for advancing the clinical management of TBI and other brain injuries.

An additional future application may be in the field of transplantation. Solid organ allografts from donation after brain death, the leading source of donor organs, have been noted to have inferior graft survival compared to those from living donors.5 Given the systemic nature of brain injury and brain death, it is likely that the organs similarly undergo immune and inflammatory responses, potentially predisposing the allograft to dysfunction post-transplantation.

 Thus, a better understanding of what happens at the cellular and molecular levels following brain injury may have wide-reaching clinical benefits. In addition to the potential to improve outcomes for patients with brain injury, the effects on post-transplantation organ function highlight the central role of basic and translational investigation in the development of novel therapies. This sentiment was probably best captured by the Noble Laureate Francis Crick (1916-2004) when he wrote “Almost all aspects of life are engineered at the molecular level, and without understanding molecules we can only have a very sketchy understanding of life itself.” What Mad Pursuit (1988).


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