Clinical Anatomical Perspective of Skull Bone Marrow's Contribution to Neuroimmune Regulation

¹Biomedical Sciences Department, College of Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates

²Neuroscience Research Center, University of Gorgia, Athene, Gorgia 30601, USA

³Biochemistry & Molecular Biology Department, Medical Research Institutes in Texas, Texas 78712, USA

⁴Department of Pharmacotherapeutics, College of Pharmacy, Immam Abdulrahman University, Dmmam 8273, KSA

⁵Neonatal Intensive Care Unit, Dr. Suliman Al Habib Medical Group, Riyadh 11635, Kingdom of Saudi Arabia

⁶Anatomy and Embryology Department, College of Medicine, Tanta University, Tanta 31511, Egypt

⁷Anatomy and Embryology Department, College of Medicine, Alexandria University, Alexandria 213511, Egypt

*Corresponding author: Prof. Ahmed Salah Ashour, Biomedical Sciences Department, College of Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates, E-mail: [email protected]

Received Date: April 29, 2025

Published Date: May 27, 2025

Citation: Ahmed AS, et al. (2025). Clinical Anatomical Perspective of Skull Bone Marrow's Contribution to Neuroimmune Regulation. Mathews J Neurol. 9(1):31.

Copyrights: Ahmed AS, et al. © (2025).

ABSTRACT

Inflammation is a protective immune response to injury or infection, promoting tissue repair and pathogen elimination. However, when it becomes dysregulated, it can worsen tissue damage, especially in brain injuries. The blood-brain barrier (BBB) typically protects the brain from immune cell infiltration, but during injuries, it can be compromised, leading to neuroinflammation and further damage. Recent research has highlighted the importance of skull bone marrow (SBM) in the brain's immune response, a concept once overlooked. SBM offer a direct pathway for immune cells to move between the skull and the brain, enhancing the brain’s immune defense. These cells, which are closer to the cerebrospinal fluid (CSF), show distinct molecular profiles that support tissue repair and immune modulation rather than promoting excessive inflammation. SBM play a key role in regulating immune responses during conditions like brain injuries, infections, and neurodegenerative diseases. Their ability to support both pro-inflammatory and anti-inflammatory responses makes them crucial for CNS immunity and recovery. The aim of this work is to investigate the role of SBM in central nervous system (CNS) immunity, particularly during brain injury, infection, and neurodegenerative disease. The current review seeks to highlight SBM's unique contribution to immune regulation and tissue repair in the brain, emphasizing its potential as a therapeutic target for modulating neuroinflammation and improving clinical outcomes in neurological disorders. Future research on skull bone marrow could lead to new therapeutic strategies for treating neurological disorders and improving clinical outcomes.

Keywords: Inflammation, Blood-Brain Barrier, Skull Bone Marrow, Neuroinflammation.

INTRODUCTION

Inflammation is a vital response of the immune system to injury or infection, aimed at repairing tissues and eliminating pathogens. However, when this inflammatory response becomes excessive or prolonged, it can lead to tissue damage and hinder recovery. In the context of brain injuries, this phenomenon is particularly concerning. The blood-brain barrier (BBB) plays a central role in protecting the brain from harmful immune cells and pathogens under normal conditions. However, during brain injuries, the BBB becomes compromised, allowing immune cells to infiltrate the brain. This infiltration can trigger neuroinflammation, which, while initially protective, can lead to worsening neurological damage if unchecked [1].

The bone marrow, traditionally considered the primary source of immune cells, has a fundamental role in this process. It produces various immune cells that circulate throughout the body and are mobilized during injury or infection. While the bone marrow’s role in immune defense has been well-established (Figure 1), its involvement in the brain’s immune response has been less clear [1]. Recent studies have raised significant questions about how immune responses are coordinated at various injury sites within the brain, especially when considering how immune cells from the bone marrow interact with the brain tissue [2].

Figure 1. Original diagram illustrates bone marrow’s role in generating immune cells like lymphocytes and macrophages, which circulate through the bloodstream and lymphatic system to reach the brain, where they contribute to immune responses at injury sites and interact with brain tissue.

Historically, the brain has been considered an immune-privileged organ, meaning it was thought to be largely isolated from the peripheral immune system to prevent inflammation that could damage delicate neural structures [2]. However, emerging research has challenged this notion, revealing a much more complex relationship between the brain and the immune system. Structures like the meninges, choroid plexus, and perivascular spaces are now recognized as crucial components in both immune surveillance and repair mechanisms within the brain [1]. The discovery of newly identified microvascular channels, known as skull bone marrow (SBM) channels, has provided further insight into this process. These channels serve as a direct communication pathway between the skull's bone marrow and the brain, allowing immune cells to migrate between these regions and thus strengthening the brain’s immune response [3].

The skull bone marrow (SBM) has emerged as a vital contributor to central nervous system (CNS) immunity, particularly under pathological conditions such as infection, ischemia, and brain injury. In these states, SBM becomes activated, increasing immune cell production and directing these cells to the meninges—the protective membranes surrounding the brain—where they help regulate immune responses and promote tissue repair [3]. Anatomical studies reveal that SBM is densely distributed throughout the frontal, parietal, and occipital regions of the skull, with species-specific differences in structure and connectivity. Notably, in humans, skull bone marrow contains larger cavities and more extensive connections to the meninges compared to those in animal models, indicating a potentially greater role in immune modulation within the human brain [1]. This structural complexity may enable more robust or nuanced immune responses during CNS stress or injury. The discovery of the SBM's active role challenges the long-standing assumption that brain immune cells are exclusively derived from peripheral sources. Instead, it highlights the skull as a local, specialized site of immune support. Recognizing the importance of SBM not only deepens our understanding of neuroimmunology but also opens new avenues for diagnostic and therapeutic strategies targeting CNS disorders, emphasizing its role in brain resilience and recovery [4].

SKULL BONE MARROW AND PERIPHERAL BONE MARROW IN CNS IMMUNITY

Bone marrow, as a site of hematopoiesis, is the primary source of the body’s immune cells, which play a pivotal role in defending against infections, repairing tissue, and maintaining homeostasis [3]. However, when considering the brain’s immune system, the contribution of skull bone marrow is distinct from that of peripheral bone marrow, particularly during pathological events such as brain injury, neuroinflammation, or infection [5].

The primary difference between skull and peripheral bone marrow lies in their anatomical proximity and access to the brain [4]. Peripheral bone marrow, located in distant bones such as the femur, pelvis, and vertebrae, is generally isolated from the brain by the BBB (Table 1). The BBB is a selective barrier that protects the brain from potentially harmful substances, including immune cells, under normal conditions [5]. This separation means that peripheral bone marrow-derived immune cells can only reach the brain under specific conditions where the BBB is compromised, such as during infection, injury, or neuroinflammation [6].

Table 1. Comparison Between SBM and Peripheral Bone Marrow (PBM) in CNS Immunity

MOLECULAR DIFFERENCES IN IMMUNE SIGNATURES

One of the most striking distinctions between skull and peripheral bone marrow is the molecular profile of the immune cells they generate. While both bone marrow sources produce a variety of immune cells, skull bone marrow-derived immune cells exhibit unique characteristics that are particularly suited to responding to CNS-specific challenges [8].

In peripheral bone marrow, immune cells like neutrophils, monocytes, and macrophages typically express high levels of pro-inflammatory molecules such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-C motif ligand 5 (CCL5) [9]. These molecules are typically associated with heightened inflammation and immune activation in response to infections or injuries [7]. However, immune cells derived from skull bone marrow show a different molecular profile [9]. They exhibit lower expression of these pro-inflammatory molecules and instead upregulate genes that are involved in tissue repair, metabolic balance, and the resolution of inflammation [4]. These observations suggest that skull bone marrow-derived immune cells are more likely to play a regulatory or immunomodulatory role (Figure 2), which is especially important during neuroinflammation, where excessive inflammation can result in additional damage to brain tissue [10].

Figure 2. Original diagram presenting peripheral bone marrow immune cells produce pro-inflammatory molecules like IL-6, TNF-α, and CCL5. In contrast, skull bone marrow-derived immune cells show lower inflammation and focus on tissue repair and inflammation resolution, suggesting a regulatory role in neuroinflammation.

This immunomodulatory role is particularly important in the context of chronic neurological diseases, where prolonged inflammation can contribute to disease progression and neurodegeneration. Studies of skull bone marrow-derived neutrophils, for example, have shown that these cells are involved in extracellular matrix organization and immune regulation, which can prevent excessive tissue damage [9]. This contrasts with peripheral neutrophils, which are often recruited to inflamed sites and exacerbate inflammation. These differences underscore the specialized functions of skull bone marrow in managing the immune response within the brain [11].

Interaction with CSF

Another critical distinction between skull bone marrow and peripheral bone marrow is their interaction with CSF, which serves as an essential medium for immune signaling in the CNS (Figure 3). CSF carries important biochemical signals that help regulate immune responses in the brain, particularly during injury or infection. Unlike peripheral bone marrow, which responds to systemic inflammatory signals, skull bone marrow is uniquely positioned to interact directly with CSF [10]. This direct access allows skull bone marrow to respond more quickly and specifically to local inflammatory cues [12].

Figure 3. Original diagram about immune signaling in the CNS involves interactions between neural and immune cells, notably microglia and astrocytes. This process regulates responses to injury and infection but, when dysregulated, contributes to neurodegenerative diseases.

During a brain injury or infection, the CSF carries signals that activate immune responses in the brain, prompting the skull bone marrow to produce immune cells such as neutrophils and macrophages. These cells then migrate to the meninges and other regions of the brain, where they help protect the CNS from further damage and promote healing. This direct communication pathway between the skull bone marrow and CSF is a key feature that distinguishes it from peripheral bone marrow. It enables the skull bone marrow to play a more integral role in the brain's immune defense, particularly under pathological conditions [13].

Future Research Directions

Immune cells originating from skull bone marrow exhibit expression of proteins implicated in synaptic signaling and immunoregulatory pathways, underscoring their role in sustaining immune homeostasis within the central nervous system. These cells demonstrate the capacity to engage with the brain’s extracellular matrix, thereby facilitating their migration and integration into the CNS microenvironment, where they contribute to the orchestration of context-specific immune responses [14]. In contrast, peripheral bone marrow-derived immune cells generally promote pro-inflammatory responses, which can exacerbate injury and prolong inflammation in the CNS. This difference in functionality suggests that skull bone marrow is more suited to meet the specialized immune needs of the brain (Figure 4), providing a more balanced and regulated immune response to injury, infection, and neurodegeneration [15].

Figure 4. Original diagram about skull bone marrow-derived immune cells express proteins involved in synaptic communication and immune regulation, supporting the brain's immune functions. Unlike peripheral cells, they avoid exacerbating inflammation, offering a more balanced response in the CNS. Future research should explore how these cells interact with CSF signals, potentially leading to new treatments for neuroinflammatory and neurodegenerative conditions, as well as brain injuries.

Given the specialized role of skull bone marrow in the immune response within the CNS, future research should focus on understanding the complex mechanisms by which skull marrow-derived immune cells interact with CSF signals [11]. Investigating how these cells influence neuroinflammation, tissue repair, and the resolution of brain injuries could lead to new therapeutic approaches that target these pathways [10]. By modulating skull bone marrow-derived immune cells or the CSF signaling pathways that regulate them, it may be possible to develop novel treatments for a wide range of neurological diseases, including neuroinflammatory disorders, neurodegenerative diseases, and traumatic brain injuries [16].

BONE MARROW-DERIVED IMMUNE CELLS AND NEUROLOGICAL DISORDERS

The specialized role of skull bone marrow in CNS immunity becomes even more significant when considering various neurological disorders. Skull bone marrow-derived immune cells exhibit unique characteristics that are particularly beneficial in managing immune responses to CNS-specific injuries or diseases [17].

Multiple Sclerosis (MS)

In MS, a chronic autoimmune disease characterized by demyelination in the CNS, skull marrow-derived immune cells play an important role in modulating inflammation. Myeloid cells from SBM, such as monocytes and neutrophils, exhibit anti-inflammatory properties that help resolve inflammation and promote tissue repair during both the acute and chronic phases of MS. This contrasts with peripheral-derived immune cells, which are typically more pro-inflammatory and contribute to the progression of disease [16]. Targeting skull bone marrow-derived immune cells in MS therapy could therefore help modulate inflammation and improve disease outcomes [18].

Stroke

Following a stroke, skull bone marrow-derived neutrophils and monocytes rapidly infiltrate the infarcted area and contribute to both the inflammatory response and recovery process [16]. These SBM-derived cells exhibit unique gene expression profiles compared to peripheral-derived immune cells, underscoring the specific role that skull bone marrow plays in stroke recovery. Understanding the unique characteristics of SBM-derived immune cells in stroke could lead to novel therapeutic strategies to enhance recovery and minimize secondary injury [19].

Traumatic Brain Injury (TBI)

Traumatic brain injury triggers a complex immune response, with both beneficial and detrimental effects. Skull marrow-derived immune cells, particularly neutrophils and monocytes, contribute to both the inflammatory response and the repair process following TBI [18]. These cells exhibit distinct phenotypes compared to peripheral-derived immune cells, highlighting the importance of skull bone marrow in managing immune responses and promoting recovery after brain injury [20].

Subarachnoid Hemorrhage (SAH)

In SAH, SBM-derived Ly6Chigh monocytes play a crucial role in mediating both inflammatory and anti-inflammatory responses, depending on the stage of the injury. Inhibiting CCL2 signaling, which is necessary for monocyte migration, impairs recovery, highlighting the dual role that SBM-derived immune cells play in both protecting the brain and promoting repair [21].

CNS Infections and Neurodegenerative Diseases

Skull bone marrow is also essential for immune responses to CNS infections, including bacterial meningitis, where it plays a key role in producing immune cells that protect the meninges and the brain. Moreover, in neurodegenerative diseases such as Alzheimer's and Parkinson's, SBM-derived immune cells influence neuroinflammation and disease progression (Table 2). Targeting these cells could provide a potential therapeutic approach to modulate immune responses in these diseases [22].

Table 2. Skull Bone Marrow-Derived Immune Cells in Neurological Disorders

Aging impacts skull bone marrow function, leading to decreased immune cell production and increased peripheral infiltration. However, skull bone marrow shows resistance to age-related decline, maintaining its ability to produce immune cells that help mitigate neuroinflammation and protect against neurodegenerative diseases [23].

CNS Tumors and Immune Response

In CNS tumors such as glioblastoma (GBM), SBM-derived neutrophils play a significant role in the tumor microenvironment. These cells differentiate into hybrid tumor-associated neutrophils (TANs) with antigen-presenting capabilities, offering potential for novel immunotherapies. Similarly, SBM is involved in the migration of tumor cells to the meninges in metastatic cancer, providing a novel target for therapeutic interventions [24].

CONCLUSION

Skull bone marrow plays a critical role in central nervous system (CNS) immunity by housing specialized immune cells that interact directly with cerebrospinal fluid (CSF), influencing neuroinflammation and neurodegeneration. Unlike peripheral marrow, skull marrow uniquely contributes to brain immune responses. Non-invasive imaging techniques such as TSPO-PET show strong potential for detecting skull marrow activity in conditions like Alzheimer’s and multiple sclerosis, offering an alternative to invasive bone marrow biopsies (Table 3). Additionally, intracalvarial drug delivery, which bypasses the blood-brain barrier, significantly enhances therapeutic delivery to the brain. This emerging approach holds promise for improving treatment outcomes in CNS disorders and warrants further investigation.

Table 3. Molecular Signatures of SBM-Derived Immune Cells vs. Peripheral Bone Marrow (PBM)-Derived Immune Cells

• Ahmed S. Ahmed: Planned designed and final review of the manuscript.
• Jim Schank: Data collection, Data analysis, discussion of idea.
• Mark M. Rohn: Data collection, Data analysis, discussion of idea.
• Asim S. Khan: Data analysis, discussion of idea.
• Ehab M. Hantash: Data analysis.
• Liju S. Mathew: Data analysis.

FUNDING

The authors declare that no funds were obtained (The current study is self-funded).

DATA AVAILABILITY

On reasonable request, the data sets generated and analyzed during the current study are available if requested from the corresponding author.

ACKNOWLEDGEMENTS

None.

CONFLICT OF INTEREST

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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