The retinal microglia and extra‐ocular inflammation
Authors: Avilés‐Trigueros Marcelino 
Published: January 2025

The nervous system is the intricate network that orchestrates integration and coordination within an organism, managing the reception, processing, and transmission of information to generate responses for regulating and sustaining homeostasis. At the centre of this complex system is the central nervous system (CNS), where haemato‐neuronal barriers act as guardians, limiting the entry of immune system cells. However, recent evidence highlights the potential impact of neuro‐immunological interactions during injury, inflammation, and chronic peripheral diseases, potentially fostering chronic neurodegenerative pathologies within the CNS.

Inflammation is emerging as a key player in both the resolution and perpetuation of CNS damage. Recent scientific endeavours have scrutinized the roles and characteristics of phagocytic cells in the CNS, particularly the contributions of different macrophage subpopulations to either excessive inflammation or beneficial repair processes after injury.

These findings beg the question: How do local peripheral neuroimmunological interactions trigger inflammatory responses within the CNS, and how can we delve deeper into this phenomenon? Exploring this intricate process in the retina, an area devoid of neural afferents from other CNS regions, presents a unique opportunity for understanding these mechanisms.

Researchers have turned to preclinical injury models involving peripheral nervous system lesions (like sciatic nerve trauma) or inflammatory lesions (such as inducing peripheral arthritic joint processes) to study the CNS's response to local peripheral inflammation in adult mice retina over time. The outcomes have unveiled qualitative and quantitative cellular shifts indicative of microglial activation processes within the retina. However, these changes have not translated significantly to alterations within its neuronal population. Notably, observations of haematic mononuclear‐phagocytic cell presence and activation of myelopoietic origin have also been noted in the retina, with these cells differentiating into microglia.

In cases where no local retinal injury occurred, it is postulated that the detected neuroinflammatory reaction could derive from a pre‐emptive CNS defence mechanism geared towards neuroprotection. Microglial cells derived from haematic monocyte/macrophage cell populations may align with the M2 macrophage subtype, known for its ability to restrain proinflammatory immune responses while fostering the expression of neuroprotective and repair‐related genes.

The intricacies of these findings underscore the complexity of neuroimmunological interactions and their far‐reaching implications for CNS health. Understanding the delicate balance between protective and detrimental responses within this context becomes paramount for devising targeted interventions for neurodegenerative disorders affecting the CNS, including those affecting the retina.

However, activation of the mononuclear phagocytic system within the retina due to peripheral inflammatory processes raises concerns regarding potential detriments for patients with neurodegenerative retinal diseases or even contributing to their onset and progression.

Thus, although the ability of the nervous system to regulate homeostasis and respond to challenges is well established, the intricate interplay between neural and immune components needs to be thoroughly investigated. By deciphering these mechanisms, targeted therapies could be developed that preserve CNS function and effectively combat neurodegenerative diseases.