International Journal of Molecular Sciences Review Inflammatory Response Mechanisms of the Dentine–Pulp Complex and the Periapical Tissues Kerstin M. Galler 1,*, Manuel Weber 2 , Yüksel Korkmaz 3 , Matthias Widbiller 1 and Markus Feuerer 4,5 1 Department of Conservative Dentistry and Periodontology, University Hospital Regensburg, 93093 Regensburg, Germany; [email protected] 2 Department of Oral and Maxillofacial Surgery, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany; [email protected] 3 Department of Periodontology and Operative Dentistry, University of Mainz, 55131 Mainz, Germany; [email protected] 4 Department for Immunology, University Hospital Regensburg, 93053 Regensburg, Germany; [email protected] 5 Regensburg Center for Interventional Immunology (RCI), University Hospital Regensburg, 93053 Regensburg, Germany * Correspondence: [email protected] Abstract: The macroscopic and microscopic anatomy of the oral cavity is complex and unique in the human body. Soft-tissue structures are in close interaction with mineralized bone, but also dentine, cementum and enamel of our teeth. These are exposed to intense mechanical and chemical stress as well as to dense microbiologic colonization. Teeth are susceptible to damage, most commonly to caries, where microorganisms from the oral cavity degrade the mineralized tissues of enamel and dentine and invade the soft connective tissue at the core, the dental pulp. However, the pulp is well-equipped to sense and fend off bacteria and their products and mounts various and intricate defense mechanisms. The front rank is formed by a layer of odontoblasts, which line the pulp chamber towards the dentine. These highly specialized cells not only form mineralized tissue but Citation: Galler, K.M.; Weber, M.; exert important functions as barrier cells. They recognize pathogens early in the process, secrete Korkmaz, Y.; Widbiller, M.; antibacterial compounds and neutralize bacterial toxins, initiate the immune response and alert other Feuerer, M. Inflammatory Response key players of the host defense. As bacteria get closer to the pulp, additional cell types of the pulp, Mechanisms of the Dentine–Pulp including fibroblasts, stem and immune cells, but also vascular and neuronal networks, contribute Complex and the Periapical Tissues. with a variety of distinct defense mechanisms, and inflammatory response mechanisms are critical Int. J. Mol. Sci. 2021, 22, 1480. for tissue homeostasis. Still, without therapeutic intervention, a deep carious lesion may lead to https://doi.org/10.3390/ijms22031480 tissue necrosis, which allows bacteria to populate the root canal system and invade the periradicular Received: 31 December 2020 bone via the apical foramen at the root tip. The periodontal tissues and alveolar bone react to the Accepted: 28 January 2021 insult with an inflammatory response, most commonly by the formation of an apical granuloma. Published: 2 February 2021 Healing can occur after pathogen removal, which is achieved by disinfection and obturation of the pulp space by root canal treatment. This review highlights the various mechanisms of pathogen Publisher’s Note: MDPI stays neutral recognition and defense of dental pulp cells and periradicular tissues, explains the different cell types with regard to jurisdictional claims in involved in the immune response and discusses the mechanisms of healing and repair, pointing published maps and institutional affil- out the close links between inflammation and regeneration as well as between inflammation and iations. potential malignant transformation. Keywords: dental pulp; odontoblast; tertiary dentine; immune response; carious lesion; pulpitis Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article 1. Introduction distributed under the terms and Although small, teeth are complex structures composed of several components with conditions of the Creative Commons unique architectural characteristics and functions (Figure1). Crown and root are made Attribution (CC BY) license (https:// of different mineralized tissues, namely enamel, dentine and cementum, encasing a soft creativecommons.org/licenses/by/ tissue, the dental pulp. The root anchors the tooth to the surrounding bony tissue via short, 4.0/). Int. J. Mol. Sci. 2021, 22, 1480. https://doi.org/10.3390/ijms22031480 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 23 Int. J. Mol. Sci. 2021, 22, 1480 2 of 23 tendon-like fibers called the periodontal ligament, which insert both into root cementum and bone.tendon-like fibers called the periodontal ligament, which insert both into root cementum and bone. Figure 1. Anatomy and physiology of the tooth. Figure 1. Anatomy and physiology of the tooth. Teeth are prone to damage, mostly by caries, periodontal disease and trauma. In Teethall are these prone cases, to microorganismsdamage, mostly leadby caries, to infection periodontal and inflammation. disease and trauma. Advanced In all methods these cases,and microorganisms materials are available lead to infection in dental and medicine inflammation. to date, whereAdvanced most methods therapies and aim at the materialsreplacement are available of in damaged dental medicine or lost structures.to date, where Yet, most oral tissuestherapies possess aim at multiple the re- means placementof of pathogen damaged recognition or lost structures. and defense, Yet, oral which tissues are possess currently multiple investigated means andof path- understood ogen recognitionin increasing and detail.defense, An which in-depth are understandingcurrently investigated of immune and reactionsunderstood of dentalin in- tissues, creasing ofdetail. cellular An andin-depth molecular understanding key players, of immune as well reactions as of temporospatial of dental tissues, patterns of cel- of defense will enable approaches to improve diagnostics as well as treatment strategies, which lular and molecular key players, as well as of temporospatial patterns of defense will en- can be more targeted, less invasive and aimed at tissue healing and regeneration rather able approaches to improve diagnostics as well as treatment strategies, which can be more than replacement. targeted, less invasive and aimed at tissue healing and regeneration rather than replace- ment. 1.1. Anatomy and Physiology of Sound Dental Tissues 1.1.1. Physiology of the Dentine-Pulp Complex 1.1. Anatomy and Physiology of Sound Dental Tissues The craniofacial tissues are mainly derived from cells of the cranial neural crest. 1.1.1. PhysiologyThese cells of the develop Dentine-Pulp in the dorsal Complex region of the neural tube and then migrate into the The1st–fourth craniofacialpharyngeal tissues are arch mainly [1]. In derived the dental from pulp, cells cranial of the neural cranial crest-derived neural crest. cells of the These cellspulpal develop neurons in the play dorsal an important region of rolethe neural in the regenerationtube and then of migrate mesenchymal into the pulp 1st– cells and fourth pharyngealodontoblasts arch [2 ].[1]. Most In the parts dental of the pulp, teeth cranial are formed neural by crest-derived cranial neural cells crest of cells, the namely pulpal neuronsdentine, play cementum, an important periodontal role in th ligamente regeneration and the of pulpalmesenchymal tissue, withpulp thecells exemption and of odontoblastsblood [2]. vessels Most and parts the of enamel the teeth [3]. are formed by cranial neural crest cells, namely dentine, cementum,The dental periodontal pulp and ligament the surrounding and the pulpal dentine tissue, (Figure with2A) the form exemption a unity, both of devel- blood vesselsopmentally and the and enamel structurally. [3]. The pulp is made of mesenchymal soft connective tissue; it Theextends dental pulp from aand central the surrounding chamber within dentine the tooth (Figure crown 2A) into form one a orunity, several both root devel- canals to the opmentallyroot and apex. structurally. During tooth The development pulp is made and of eruption, mesenchymal the presence soft connective of functional tissue; pulp it tissue is extends afrom prerequisite a central forchamber the completion within the of toot rooth formation. crown into The one pulp or several is lined root with canals a layer to of highly the root specializedapex. During cells, tooth the development odontoblasts and (Figure eruption,2B). These the presence post-mitotic, of functional polarized pulp cells secrete tissue is a prerequisite collagenous for matrix, the completion which later ofmineralizes root formation. to form The pulp dentine. is lined This with formative a layer process of highlyoccurs specialized physiologically cells, the odontoblasts and continuously, (Figure not2B). onlyThese during post-mitotic, tooth development polarized cells (primary secrete adentine) collagenous but alsomatrix, later which in life later (secondary mineralizes dentine). to form Each dentine. cell leaves This a formative process behind, pro- which cess occursbecomes physiologically embedded and in the continuously, mineralized not tissue, only giving during dentine tooth itsdevelopment tubular structure. (pri- While mary dentine)its composition but also later is similar in life to (secondary that of bone, dentine). and odontoblasts Each cell leaves share a many process characteristics behind, with which becomesthe osteoblasts, embedded there in arethe amineralized number of distincttissue,