Teeth are vulnerable to structural compromise, primarily attributed to carious lesions, in which microorganisms originating from the oral cavity deteriorate the mineralized structures of enamel and dentin, subsequently infiltrating the underlying soft connective tissue, known as the dental pulp. Nonetheless, dental pulp possesses the necessary capabilities to detect and defend against bacteria and their by-products, using a variety of intricate defense mechanisms. The pulp houses specialized cells known as odontoblasts, which encounter harmful substances produced by oral bacteria. These cells identify pathogens at an early stage and commence the immune system response. As bacteria approach the pulp, various cell types within the pulp, such as different immune cells, stem cells, fibroblasts, as well as neuronal and vascular networks, contribute a range of defense mechanisms. Therefore, the immune system is present in the healthy pulp to restrain the initial spread of pathogens, and then in the inflamed pulp, it prepares the conditions for necrosis or regeneration, so inflammatory response mechanisms play a critical role in maintaining tissue homeostasis. This review aims to consolidate the existing literature on the immune system in dental pulp, encompassing current knowledge on this topic that explains the diverse mechanisms of recognition and defense against pathogens exhibited by dental pulp cells, elucidates the mechanisms of innate and adaptive immunity in inflamed pulp, and highlights the difference between inflamed and normal pulp tissue.

BACKGROUND:Macrophages in the peripheral nervous system are key players in the repair of nerve tissue and the development of neuropathic pain due to peripheral nerve injury. However, there is a lack of information on the origin and morphological features of macrophages in sensory ganglia after peripheral nerve injury, unlike those in the brain and spinal cord. We analyzed the origin and morphological features of sensory ganglionic macrophages after nerve ligation or transection using wild-type mice and mice with bone-marrow cell transplants. METHODS:After protecting the head of C57BL/6J mice with lead caps, they were irradiated and transplanted with bone-marrow-derived cells from GFP transgenic mice. The infraorbital nerve of a branch of the trigeminal nerve of wild-type mice was ligated or the infraorbital nerve of GFP-positive bone-marrow-cell-transplanted mice was transected. After immunostaining the trigeminal ganglion, the structures of the ganglionic macrophages, neurons, and satellite glial cells were analyzed using two-dimensional or three-dimensional images. RESULTS:The number of damaged neurons in the trigeminal ganglion increased from day 1 after infraorbital nerve ligation. Ganglionic macrophages proliferated from days 3 to 5. Furthermore, the numbers of macrophages increased from days 3 to 15. Bone-marrow-derived macrophages increased on day 7 after the infraorbital nerve was transected in the trigeminal ganglion of GFP-positive bone-marrow-cell-transplanted mice but most of the ganglionic macrophages were composed of tissue-resident cells. On day 7 after infraorbital nerve ligation, ganglionic macrophages increased in volume, extended their processes between the neurons and satellite glial cells, and contacted these neurons. Most of the ganglionic macrophages showed an M2 phenotype when contact was observed, and little neuronal cell death occurred. CONCLUSION:Most of the macrophages that appear after a nerve injury are tissue-resident, and these make direct contact with damaged neurons that act in a tissue-protective manner in the M2 phenotype. These results imply that tissue-resident macrophages signal to neurons directly through physical contact.

ABSTRACT:Dental pulp tissue is densely innervated by afferent fibers of the trigeminal ganglion. When bacteria cause dental decay near the pulpal tissue, a strong neuronal and immune response occurs, creating pulpitis, which is associated with severe pain and pulp tissue damage. Neuroimmune interactions have the potential to modulate both the pain and pathological outcome of pulpitis. We first investigated the role of the neuropeptide calcitonin gene-related peptide (CGRP), released from peptidergic sensory afferents, in dental pain and immune responses by using Calca knockout (Calca -/- ) and wild-type (Calca +/+ ) mice, in a model of pulpitis by creating a mechanical exposure of the dental pulp horn. We found that the neuropeptide CGRP, facilitated the recruitment of myeloid cells into the pulp while also increasing spontaneous pain-like behavior 20% to 25% at an early time point. Moreover, when we depleted neutrophils and monocytes, we found that there was 20% to 30% more sensory afferent loss and increased presence of bacteria in deeper parts of the tissue, whereas there was a significant reduction in mechanical pain response scores compared with the control group at a later time point. Overall, we showed that there is a crosstalk between peptidergic neurons and neutrophils in the pulp, modulating the pain and inflammatory outcomes of the disease.

Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E (PGE) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.

The ability of the nervous system to sense environmental stimuli and to relay these signals to immune cells via neurotransmitters and neuropeptides is indispensable for effective immunity and tissue homeostasis. Depending on the tissue microenvironment and distinct drivers of a certain immune response, the same neuronal populations and neuro-mediators can exert opposing effects, promoting or inhibiting tissue immunity. Here, we review the current understanding of the mechanisms that underlie the complex interactions between the immune and the nervous systems in different tissues and contexts. We outline current gaps in knowledge and argue for the importance of considering infectious and inflammatory disease within a conceptual framework that integrates neuro-immune circuits both local and systemic, so as to better understand effective immunity to develop improved approaches to treat inflammation and disease.