In:
Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6639 ( 2023-03-31)
Abstract:
There is growing evidence that neuroimmune interactions regulate immune and inflammatory responses. In particular, nociceptors, the afferent neurons that transmit the sensation of pain or itch in response to noxious stimuli, modulate immune cell functions in the peripheral tissues that they innervate. One of the major nociceptor targets are dendritic cells (DCs), which orchestrate local inflammatory responses and control adaptive immunity. Although nociceptors have been shown to exert control over DCs in several pathophysiological settings, the molecular mechanisms underlying nociceptor–DC cross-talk and the full scope of nociceptor involvement in DC immunobiology remain to be established. RATIONALE To determine the communication framework between nociceptors and DCs, we established an in vitro coculture system for the two cell types that enabled us to interrogate bona fide nociceptor–DC interactions without the involvement of other cell types. We explored the impact of nociceptors on both activated and steady-state DCs and defined, at the molecular level, communication pathways that rely on either physical cell–cell contact or nociceptor-derived soluble mediators. Subsequently, we investigated whether key observations in our reductionist in vitro system were predictive of the nociceptor–DC dialogue in several in vivo scenarios. RESULTS We identified three molecularly distinct modalities of communication used by nociceptors to control DC functions in a context-dependent manner. First, through the production of the chemokine CCL2, nociceptors can attract DCs and regulate their tissue dwell time. Second, through the activation-induced release of the neuropeptide calcitonin gene–related peptide (CGRP), nociceptors induce a transcriptional program in DCs characterized by the expression of Il1b as well as multiple other genes important for pathogen resistance and sentinel functions, but no overt DC activation. Third, through direct electrical coupling, firing nociceptors trigger a Ca 2+ flux and membrane depolarization in DCs and potentiate DC responses to inflammatory stimuli such as Toll-like receptor (TLR) agonists. Accordingly, in vivo activation of dermal nociceptors enhanced the sentinel phenotype of DCs in the absence of immune stimuli and amplified DC-dependent tissue inflammation in response to TLR agonists. Furthermore, conditional ablation of CCL2 in nociceptors compromised the ability of dermal DCs to amplify local inflammation in the skin and to initiate adaptive immune responses against skin-derived antigens. CONCLUSION The multiple communication modalities characterized here reveal how nociceptors and DCs form a neuroimmune unit that integrates the nociceptors’ rapid responsiveness and finely honed ability to sense and respond to noxious stimuli with the DCs’ ability to coordinate innate and adaptive immune responses. This merger of unique capabilities allows the nociceptor–DC unit to act as an advanced warning system. DCs in barrier tissues are therefore a priori primed to anticipate imminent pathogen encounter, respond more vigorously upon painful pathogen exposure, and fine-tune the subsequent orchestration of adaptive immune responses to peripheral antigens. Nociceptors communicate with dendritic cells (DCs) using three distinct pathways to elicit context-dependent responses. (i) The release of CCL2 attracts DCs and regulates their dwell time within barrier tissues and antigen transport to lymph nodes; (ii) pain-induced release of the neuropeptide CGRP alters the transcriptional profile of steady-state DCs to assume enhanced sentinel functions; and (iii) when activated DCs contact firing nociceptors, the electrical activity amplifies their proinflammatory cytokine response. IL-6/12/23, interleukin-6, interleukin-12, interleukin-23.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abm5658
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2023
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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