Multimodal control of dendritic cell functions by nociceptors

Abstract

It is known that interactions between nociceptors and dendritic cells (DCs) can modulate immune responses in barrier tissues. However, our understanding of the underlying communication frameworks remains rudimentary. Here, we show that nociceptors control DCs in three molecularly distinct ways. First, nociceptors release the calcitonin gene–related peptide that imparts a distinct transcriptional profile on steady-state DCs characterized by expression of pro–interleukin-1β and other genes implicated in DC sentinel functions. Second, nociceptor activation induces contact-dependent calcium fluxes and membrane depolarization in DCs and enhances their production of proinflammatory cytokines when stimulated. Finally, nociceptor-derived chemokine CCL2 contributes to the orchestration of DC-dependent local inflammation and the induction of adaptive responses against skin-acquired antigens. Thus, the combined actions of nociceptor-derived chemokines, neuropeptides, and electrical activity fine-tune DC responses in barrier tissues.

The role of dendritic cells in MASH: friends or foes?

“…Resting DCs receive environmental signals (e.g., type I IFNs) that maintain their homeostasis and survival ( 25 , 26 ). cDCs are able to sense the environment via innate immune receptors such as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) or respond to various cytokines (e.g., Il1β) ( 27 , 28 ).…”

Bidirectional crosstalk between the peripheral nervous system and lymphoid tissues/organs

“…After the immunostaining step, optic sectioning and 3D projection/reconstruction might reveal neuroimmune interactions in situ , thereby excluding the possibility of the “random colocalization” of nerve fibers and immune cells ( 173 ) and establishing that two structures have actual close contact (not attributable to their merely lying near each other or to the viewpoint/resolution limit of the light microscopy). Second, live cell/tissue/organ/animal imaging ( 174 , 175 ) should be used to study this type of dynamic interaction between nerve fibers and immune cells. Third, this type of contact needs to be confirmed further in tissue sections/co-culture of neurons/glial cell and immune cells by using EM and immuno-EM as described in a few previous studies ( 175 , 176 ).…”

“…Second, live cell/tissue/organ/animal imaging ( 174 , 175 ) should be used to study this type of dynamic interaction between nerve fibers and immune cells. Third, this type of contact needs to be confirmed further in tissue sections/co-culture of neurons/glial cell and immune cells by using EM and immuno-EM as described in a few previous studies ( 175 , 176 ). Once enough anatomical/morphological evidence of nerve-immune cell interaction has been obtained, further molecular/physiological/functional studies should be conducted to reveal the molecular mechanism of this type of local neuroimmune interaction ( 20 , 177 – 179 ).…”

“…Neuroimmune cell units typically involve specific immune cells (e.g., microglia, B/T cells, mast cells, DCs, macrophages) interacting with neurons/nerves and other glial cells. These interactions, occurring through the formation of physical contacts or synapse-like connections ( 36 , 175 , 180 ), involve the exchange of signaling molecules, including cytokines, chemokines, neurotransmitters, and other immune modulators. Neuroimmune cell units are thought to play a significant role in regulating neuroinflammatory responses, modulating neuroimmune signaling, and influencing disease progression in various neurological/neurological disorders and cancers.…”

TRPV1 nociceptors are required to optimize antigen-specific primary antibody responses to novel antigens

“…By binding to cognate receptors on immune cells, these neuropeptides induce changes in cytokine production, immune cell transcriptome, and immune phenotype (Pinho-Ribeiro et al 2017 ). Recent studies have also appreciated that TRPV1 + nociceptors are present in close proximity to dendritic cells (DC), and physically interact with DCs to modulate its function (Cohen et al 2019 ; Kashem and Kaplan 2016 ; Kashem et al 2015 ; Huang et al 2021 ; Hanč et al 2023 ). By releasing specific neuropeptides, nociceptors also regulate Th2 and Th17 type immune responses.…”