Guardians of the Gateway: The Pivotal Role of Macrophages in the Blood-DRG Barrier


Macrophages are versatile cells of the immune system, present in virtually every tissue. They are known for their roles in phagocytosing cellular debris and orchestrating tissue repair. However, their tissue-specific functions, which are dictated by their microenvironment, are diverse and complex. Macrophages in the central nervous system (CNS), particularly the parenchymal microglia and border-associated macrophages, have been extensively studied. However, peripheral sensory nervous system macrophages, particularly those in the DRG, are less understood in terms of their transcriptional heterogeneity, ontogeny, regulation by the microenvironment, and homeostatic functions. The blood-nerve barrier (BNB) and the blood-brain barrier (BBB) share several characteristics, including low transcytosis levels, tight junction proteins, and absence of endothelial fenestrae. The neuronal cell bodies in the DRG are supplied by a more permeable vascular bed than the axons in the peripheral nerve. The mechanisms regulating endothelial permeability at the blood-DRG barrier, and the role of macrophages in this context, have remained unexplored until now.

In a new collaborative study published in Journal of Experimental Medicine and led by Professor Camilla Svensson from the Karolinska Institutet in Sweden, explored the role of macrophages in the dorsal root ganglia (DRG), particularly their interactions with the vasculature. This research is pivotal in expanding our understanding of macrophage functions beyond their established roles in pain, nerve injury, and repair. The authors found most DRG macrophages to closely interact with the vasculature, actively sampling macromolecules from the blood. The endothelial cells in the DRG displayed a unique transformation along the arteriovenous axis, both structurally and functionally, with varying molecular, structural, and permeability properties. Using scRNA-seq to analyze the transcriptomic profiles of DRG macrophages, revealing distinct subsets based on gene expression, they identified two subsets of perivascular macrophages: CD163+ macrophages were found to be self-maintaining and primarily involved in monitoring the vasculature. They showed distinct transcriptomic profiles, turnover, and responses during peripheral inflammation. The team employed Cav1 knockout mice to investigate the role of caveolar transcytosis in endothelial cells and its impact on macrophage function. The study highlighted the role of enhanced caveolar transcytosis in endothelial cells in regulating endothelial permeability and its alignment with macrophage phagocytosis. Intravenous injection of various tracer molecules was conducted to study the phagocytic activity of DRG macrophages and their ability to sample macromolecules from the blood. The findings provided a molecular explanation for the permeability characteristics of the blood-DRG barrier and underscored the integral role of macrophages in the DRG-neurovascular unit.

The researchers demonstrated that most DRG macrophages interact closely with the vasculature, sampling macromolecules from the blood. This interaction is facilitated by a specialized endothelial bed in the DRG, which undergoes transformation along the arteriovenous axis. The endothelial bed in the DRG is characterized by distinct molecular, structural, and permeability properties. This bed is covered by macrophage-interacting pericytes and fibroblasts. They also observed that macrophage phagocytosis aligns spatially with peak endothelial permeability, regulated by enhanced caveolar transcytosis in endothelial cells. The authors identified two subsets of perivascular macrophages in the DRG with unique transcriptomes, turnover, and functions. The CD163+ macrophages are highlighted for their role in vasculature monitoring. The findings provide a molecular explanation for the permeability of the blood-DRG barrier, highlighting the unappreciated role of macrophages as integral components of the DRG-neurovascular unit.

In summary, the new comprehensive study by Professor Svensson and her team highlights the complexity and specificity of macrophage functions in the DRG, particularly in relation to the vasculature. It opens new avenues for understanding how the immune system interfaces with the nervous system, particularly in the context of peripheral sensory neurons. This knowledge has significant implications for our understanding of sensory disorders, pain management, and the development of targeted therapies.

Guardians of the Gateway: The Pivotal Role of Macrophages in the Blood-DRG Barrier - Medicine Innovates
Image Credit: J Exp Med. 2024 Feb 5;221(2):e20230675.

About the author

Camilla I. Svensson, Ph.D.

Adjunct Associate Professor, Anesthesiology
University of California, San Diego
Professor, Department of Physiology and Pharmacology
Karolinska Institutet, Stockholm, Sweden

The focus of my research is centered on joint pain in rheumatic conditions, using models of rheumatoid arthritis (RA), based on injection of collagen type II antibodies or anti-citrullinated protein antibodies (ACPA) isolated from RA patients’ blood or generated from RA patients’ B-ceAntibody-induced pain precedes onset of inflammation. This observation is interesting considering that arthralgia and presence of serum autoantibodies predate development of RA by years in humans. Thus, I am exploring if antibodies are directly activating sensory neurons in the absence of inflammation and/or trigger other cells to release factors that activate nociceptors in the joint. I have data indicating that ACPA activate osteoclasts causing release of the CXCL1 (mouse analogue to human IL-8), and that CXCR1 antagonists attenuate ACPA-induced pain-like behavior. My work points to the role of peripheral and central Fc-gamma receptors in RA-induced pain and, for this purpose, we have developed transgenic mice and associated tools to be used in efforts to decipher the role of the different Fc-gamma receptors in pain signaling.

Pain-like behavior in these models persists for an extended period, and in the case of development of joint inflammation, outlasts signs of inflammation by many weeks. This suggests that exposure to certain autoantibodies, with or without a period of joint inflammation, initiates long-term changes in the sensory system. Accordingly, a major focus is to decipher mechanisms that maintain antibody-induced long-term pain, and we have data that indicate that certain autoantibodies activate components of programs associated with neuropathic pain.

I am a professor in the Department of Physiology at the Karolinska Institute. Since 2015, I have been an adjunct associate professor in Anesthesiology at UCSD and spend 2-3 months/year at UCSD. I have collaborative grants and funding thought UCSD. This enables me to have close collaborations with investigators at UCSD and to co-supervise Ph.D. students and postdoctoral fellows.


Lund H, Hunt MA, Kurtović Z, Sandor K, Kägy PB, Fereydouni N, Julien A, Göritz C, Vazquez-Liebanas E, Andaloussi Mäe M, Jurczak A, Han J, Zhu K, Harris RA, Lampa J, Graversen JH, Etzerodt A, Haglund L, Yaksh TL, Svensson CI. CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier. J Exp Med. 2024 Feb 5;221(2):e20230675. doi: 10.1084/jem.20230675.

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