The neuroimmune connectome in health and disease

Abstract

The nervous and immune systems have complementary roles in the adaptation of organisms to environmental changes. However, the mechanisms that mediate cross-talk between the nervous and immune systems, called neuroimmune interactions, are poorly understood. In this Review, we summarize advances in the understanding of neuroimmune communication, with a principal focus on the central nervous system (CNS): its response to immune signals and the immunological consequences of CNS activity. We highlight these themes primarily as they relate to neurological diseases, the control of immunity, and the regulation of complex behaviours. We also consider the importance and challenges linked to the study of the neuroimmune connectome, which is defined as the totality of neuroimmune interactions in the body, because this provides a conceptual framework to identify mechanisms of disease pathogenesis and therapeutic approaches. Finally, we discuss how the latest techniques can advance our understanding of the neuroimmune connectome, and highlight the outstanding questions in the field.

Fig. 1 |. Neuroimmune interactions in inflammation and neurodegeneration.

Selected neuroimmune interactions and their effects on tissue pathology. ACh, acetylcholine; TH, tyrosine hydroxylase; Tr1, type 1 regulatory T cell.

Fig. 2 |. Brain areas responsive to immune cues.

Brain nuclei and the mechanisms that regulate them in the context of immunological or behavioural perturbations. γδ T cell, γδ TCR-expressing T cell; GBRA1, GABA_A receptor subunit 1; GDF15, growth/differentiation factor 15; Ly6C^hi, pro-inflammatory monocyte; MMP8, matrix metalloproteinase 8; mPFC, medial prefrontal cortex; PGE2, prostaglandin E2.

Fig. 3 |. Environmental regulation of the neuroimmune connectome.

Environmental factors, such as the host microbiome and environmental chemicals, modulate immune and neural cell responses throughout the body. The schematic shows the host microbiome influencing multiple tissues, including the lung and intestines, and producing microbial metabolites that signal to the brain. AHR, aryl hydrocarbon receptor; APC, antigen-presenting cell; SCFA, short-chain fatty acid; Trp, tryptophan.

Fig. 4 |. Technologies used to study neuroimmune interactions.

Many tools exist that have great potential to decipher neuroimmune interactions, but each class of technologies possesses unique strengths and weaknesses. Actuator technologies provide excellent temporal and spatial resolution but lack detailed longitudinal molecular information on the cells targeted (such as the transcriptome). Specialized methods to study cell–cell communication enable connectome studies linked to molecular data but lack high temporal resolution. Visualization strategies enable systematic anatomical mapping but provide only a snapshot of cellular dynamics and are limited in the number of read-out channels. Technologies to investigate cell states enable specialized molecular and temporal analyses but have low spatial resolution. AAV, adeno-associated virus.