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Researchers reviewed current knowledge and outstanding questions regarding how neuroimmune crosstalk shapes allergic inflammation onset and progression.

A recent review in Annual Review of Immunology by Caroline Sokol, MD, PhD, Massachusetts General Hospital, and colleagues elucidated current knowledge and outstanding questions regarding how neuroimmune crosstalk critically shapes the initiation and progression of allergic inflammation.

The authors explained that the intricate dialogue between the nervous and immune systems is evolutionarily conserved and deploys sophisticated mechanisms to mount balanced defenses against environmental insults such as allergens and tissue injury.

Mechanisms of Neuroimmune Interaction

According to the authors, the four principal modes of neuroimmune interaction are:

• Direct cell–cell contact;
• Mitochondrial transfer;
• Extracellular vesicle exchange; and
• Signaling via soluble factors.

“While soluble factors such as neuropeptides, neurotransmitters, and cytokines play critical roles in neuroimmune communication, key questions remain,” the authors wrote. “Do these factors encode the entirety of the message, or do they act as contextual signals for interpreting other stimuli?” They emphasized that dissecting how discrete neuron–immune cell pairings form localized communication units—and how distinct neuronal subpopulations orchestrate allergic responses—will be essential. Moreover, alternative modes of communication—such as mitochondrial transfer, vesicle-mediated transfer, or yet undiscovered pathways—warrant further exploration.

Sensory Neurons & Allergen Detection

The review highlighted the paradigm-shifting discovery that sensory neurons in barrier tissues can directly detect allergens, thereby initiating type 2 immune responses that are distinct from the innate recognition of bacterial or viral structures. However, the authors noted, key questions persist: How do neurons discriminate among diverse allergens? And how do peripheral immune cues integrate with—or modulate—central nervous system signaling? Addressing these questions could redefine our understanding of allergen sensing and early inflammatory triggers.

Modulators of Neuroimmune Circuits

“Our understanding of how local and systemic factors shape the neuroimmune interactions is in its infancy,” the authors stated. “External and internal influences, such as stress, circadian rhythms, microbiota, and aging, clearly modulate neuroimmune circuits and the incidence or severity of allergic diseases. However, the underlying cellular and molecular mechanisms remain largely unknown.”

The authors proposed that uncovering how neuroimmune communication modules adapt to varying physiological states and environmental stimuli may clarify why some individuals are predisposed to allergic conditions or systemic reactions, such as anaphylaxis.

“Appreciating neuroimmune communications as an evolutionarily conserved and functionally integrated system that is fundamentally involved in type 2 immunity will provide new insights into allergic inflammation and reveal exciting opportunities for the management of acute and chronic allergic diseases,” the authors concluded.