In vitro, the presence of nociceptors (pain-sensing neurons) enhanced the DC cytokine response to diverse pathogens or TLR agonists and altered DC transcriptional states. Nociceptor-secreted CCL2 and calcitonin gene-related peptide (CGRP) induced DC migration and pro-IL-1B accumulation, respectively, and the two cell types displayed close physical interactions. Nociceptors also supported DC calcium flux after capsaicin-induced membrane depolarization in nociceptors. In mice, depletion or inhibition of nociceptors muted DC response to imiquimod stimulation, and loss of CCL2 reduced dermal DC numbers, activation, and antigen trafficking.
Contributed by Alex Najibi
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.
Author Info: (1) Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. (2) Department of Immunology, H
Author Info: (1) Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. (2) Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. (3) Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. (4) Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. (5) Cell Biology Microscopy Facility, Harvard Medical School, Boston, MA 02115, USA. (6) Departments of Chemistry, Molecular & Cell Biology, and Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA. (7) Departments of Chemistry, Molecular & Cell Biology, and Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA. (8) Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. The Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
