ACTIVATION OF THE PD-1/PD-L1 AXIS INHIBITS PRO-INFLAMMATORY CYTOKINES PRODUCED BY MICROGLIA AND CONTROLS NEUROINFLAMMATION

Letter to the Editor

A. Caraffa^*

INRCA Istituto Nazionale di Ricovero e Cura per Anziani, Ancona, Italy.

*Correspondence to:
Alessandro Caraffa,
INRCA Istituto Nazionale di Ricovero e Cura per Anziani,
Ancona, Italy.
e-mail: alecaraffa@libero.it

Received: 11 May, 2026 Accepted: 17 June, 2026

ISSN 2279-5855 print / 3103-7364 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

KEYWORDS: PD-1, PD-L1 axis, neuroinflammation, microglia, CNS

INTRODUCTION

Activation of programmed cell death protein 1 (PD-1) with its ligand PD-L1 plays a key role in the brain (1).  PD-1 controls both neuroimmune mechanisms and inflammation, preventing irreversible neuronal damage, especially since neurons have limited regenerative capacity (2). PD-1 controls the activation of T lymphocytes and contributes to brain immune privilege; that is, the ability of certain tissues to limit local immune responses to protect particularly vulnerable structures. PD-1 is also involved in the function of microglia, resident immune cells of the central nervous system (CNS). Endothelial cells of the blood-brain barrier (BBB) and some neurons produce PD-1. Expression increases during inflammation, infections, elevated interferon gamma (IFN-γ), and neurodegeneration, but it is primarily expressed by resident and/or infiltrating T lymphocytes (3).

DISCUSSION

PD-1 limits neuroinflammation in the CNS. PD-1 activated by PD-L1 is released by glia and endothelial cells (4).  PD-1 reduces T cell proliferation, resulting in decreased production of IFN-γ and tumor necrosis factor (TNF), and protection of neurons. This mechanism is important in several diseases of the brain, including encephalitis, viral infections of the CNS, and multiple sclerosis. Dysregulation of PD-1 can increase the activity of autoreactive T cells and cause autoimmune disease.

Tumor cells also possess PD-1 receptors and express PD-L1 (5,6). In glioblastoma, cells overexpress PD-L1, and T lymphocytes become exhausted in an immunosuppressive environment. Anti-PD-1 and anti-PD-L1 antibodies have been used experimentally in these cases. In experimental animal models, some studies suggest that blocking PD-1 results in increased neuronal excitability, possible cognitive improvement, and changes in pain perception (7).

Microglia can express PD-1 and its ligands PD-L1 and PD-L2, modulating neuroinflammation and neurodegeneration. Activation of PD-1 regulates microglial activation and inhibits the production of pro-inflammatory cytokines, establishing an immunosuppressive state. Immunosuppression is an important and necessary biological process in neurological diseases where excessive immunity causes conditions such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, and COVID-19 neuroinflammation, amongst others (8).

Microglia are similar to M1 macrophages. Like these, when activated, they can produce pro-inflammatory M1 cytokines such as IL-1β, TNF, IL-6, IL-18, and others. Microglia can also produce chemokines such as MCP-1 and CXCL10. Both cytokines and chemokines increase neuroinflammation, recruit immune cells, and contribute to neuronal damage. However, microglia also produce anti-inflammatory cytokines, an effect that no longer aims to destroy the pathogen but to limit collateral damage and promote the recovery of tissue.

Signals produced by astrocytes and neurons cause microglia to change their program and produce anti-inflammatory proteins such as IL-4, IL-10, TGF-β, and PD-1 (9). Following these signals, microglia reduce the activation of inflammatory pathways such as NF-κB and MAPK and reduce the effect of reactive oxygen species (ROS), nitrous oxide (NO), and pro-inflammatory cytokines. Furthermore, these circumstances can stimulate the phagocytosis of cellular debris and synaptic remodelling, which protects neurons and promotes tissue repair. Microglia without danger signals tend to produce anti-inflammatory cytokines and protect brain tissue by eliminating myelin debris, apoptotic neurons, and reducing damaged synapses.

Healthy neurons maintain microglia in a regulatory quiescent state through signals such as CX3CL1, CD200, and physiological purinergic signals. These promote very low production of inflammatory cytokines and promote anti-inflammatory mediators. Preventing chronic CNS inflammation is crucial, as neurons have limited regenerative capacity. Therefore, after injury or infection, microglia often switch from a pro-inflammatory to a regulatory state to limit neuronal damage. In some experimental models, blocking PD-1 can increase immune activity in the CNS, reactivate microglia, and promote the clearance of pathological aggregates, but it can also worsen neuroinflammation and induce neuronal toxicity (10).

CONCLUSIONS

PD-1 activation plays a fundamental role in modulating the immune and inflammatory response in the brain. Inhibiting the production of pro-inflammatory cytokines by microglia contributes to the control of neuroinflammation and the maintenance of neuronal homeostasis. The PD-1/PD-L1 axis represents a promising therapeutic target in neuroinflammatory and neurodegenerative diseases.

Conflict of interest

The author declares that they have no conflict of interest.

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