Correspondence: Dr LO Bakaletz, The Research Institute at Nationwide Children's Hospital, Center for Microbial Pathogenesis, The Ohio State University College of Medicine, 700 Children's Drive, Rm W591, Columbus, OH 43205, USA. E-mail: Lauren.Bakaletz@NationwideChildrens.org

The inflammatory response is a critical mechanism used by multicellular organisms to protect themselves from cellular damage caused by microorganisms or other stimuli. In a dysregulated state, inflammation can also contribute to the chronicity of debilitating conditions such as cystic fibrosis, Crohn's disease and asthma.¹ In a recent study published in Immunology and Cell Biology, Pingel et al.² have provided evidence of a novel mechanism used by the host to dampen the inflammatory response observed during periodontal disease (Figure 1) that can result because of the presence of pro-inflammatory bacterial molecules. This dampening process is likely to contribute to maintaining tissue homeostasis and might further lend itself to manipulation to better treat this painful, debilitating and unsightly condition.

Figure 1.

Advanced periodontitis. Image reproduced with permission from http://www.enexus.com/gumdisease/ 1995–2005 Enexus Inc.

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Both the host, and microbes that colonize its mucosal surfaces, have developed remarkable strategies to control and limit the inflammatory response, each to their own benefit (Figure 2). Porphyromonas gingivalis is a predominant etiological agent of periodontal disease, a chronic polymicrobial inflammatory disease of the gingiva and surrounding tissue that ultimately leads to tooth loss. This microorganism expresses an impressive array of proteases, destructive enzymes and adhesins such as the hemagglutinin B protein.³ In addition, P. gingivalis utilizes several means to evade the immune response such as production of lipopolysaccharide (LPS) that is significantly less inflammatory than LPS of other microorganisms of the oral cavity.³

Figure 2.

Mechanisms used by the host and bacteria to dampen the inflammatory response. The highlighted text emphasizes the host strategy used to control inflammation as discussed in the study by Pingel et al.²

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Inflammation is induced when stimuli such as bacterial LPS, lipotechoic acid, or muramyl dipetide binds to host cell receptors, which subsequently initiates a series of signal-transducing events that culminate in the increased expression of pro-inflammatory molecules, such as the lipid-derived leukotrienes and specific cytokines. At several key points in this process, mechanisms are employed by the host to maintain tight control of inflammation and thereby avoid a dysregulated response. Inflammation can be modulated by affecting the expression of genes that encode inflammatory mediators and altering the stability of encoded mRNAs for some of these molecules.¹ In addition, the host can produce negative regulators of cytosolic signal transduction proteins, control the amount and location of surface receptors that engage inflammatory stimuli, and secrete molecules that bind stimulants before they engage signal-transducing receptors.⁴ As an example of the latter mechanism, a small number of human antimicrobial peptides (APs) can bind and neutralize bacterial LPS, thus dampening the inflammatory response at the source of the stimulus.⁵

Most APs are small (18–45 amino acids) cationic proteins of the innate immune system that are classified into two major families, the defensins and the cathelicidins. These proteins are produced by epithelial cells of the respiratory and oral mucosa and typically have anti-viral, anti-fungal and/or anti-bacterial properties.⁵ It has been suggested that APs be renamed 'host defense peptides' which summarizes the growing appreciation for the diverse and multi-functional activities that these proteins possess beyond their microbicidal properties. For instance, human -defensin-3 (hBD-3) is chemotactic for, and activates, specific subsets of monocytes and dendritic cells, professional antigen-presenting cells whose activities provide a bridge between the innate and adaptive arms of the immune system.⁶

Now, Pingel et al.² have uncovered evidence that hBD-3 possesses a novel activity whereby by targeting and binding to a potent bacterial activator of the inflammatory response, it can abrogate this effect. The authors demonstrated by biosensor analysis that hBD-3 bound to a recombinant form of the P. gingivalis non-fimbrial adhesin HagB (rHagB). Neither human -defensin-1 nor human -defensin-2 interacted with this adhesin, which showed that the ability to bind rHagB was not a general property shared indiscriminately by other APs of this family.

What is the effect of rHagB alone, or the interaction between rHagB and hBD-3, on the inflammatory response of cells cultured in vitro? In the cited study, both oral keratinocytes and myeloid dendritic cells increased expression of pro-inflammatory cytokines in the presence of rHagB compared with cells treated with PBS alone. In contrast, out of a panel of 22 cytokines tested, dendritic cells incubated in the presence of both rHagB and hBD-3 produced significantly reduced amounts of the pro-inflammatory cytokines IL-6, IL-8 and TNF-.² To begin to unravel the molecular pathways responsible for this dampened inflammatory response, the authors demonstrated that expression of the extracellular signal-regulated kinases, but not p38 or c-Jun N-terminal kinases, was diminished in dendritic cells incubated with hBD-3 and rHagB when compared with cells incubated with rHagB alone. An exciting question that remains is what is the ultimate fate of the hBD-3-rHagB 'complexes'? And, if they are to be degraded, what are the cellular pathways involved in this process?

Although the study by Pingel et al.² has been discussed primarily from the standpoint of host-derived benefits gained from maintaining tight control of inflammation, for normal flora (and even those that can behave as opportunistic pathogens when conditions are optimal for them to do so), keeping the host inflammatory response at bay can have distinct advantages.² Once a disease process is initiated, members of the normal bacterial flora, which are generally well-tolerated by their mammalian hosts, are now targeted for elimination as part of the immune response. To avoid immune-mediated clearance, bacteria have evolved countermeasures for immune evasion. One recent example is the ability of nontypeable Haemophilus influenzae (another commensal opportunist) to decorate the endotoxin contained in its outer membrane with phosphorylcholine stolen from its host. Such decoration not only decreases the early inflammatory response, but also delays clearance of this bacterium from the airway.^{7, 8, 9}

Collectively, the data presented in the study by Pingel et al.² also provide evidence that dysregulation of hBD-3 could be associated with the severe inflammation observed in periodontal disease and, conversely, therapeutic intervention through exogenous delivery of hBD-3 may provide a benefit to those who suffer from this chronic infection. Important litmus tests for this hypothesis will be to determine if hBD-3 can reduce the inflammatory response of dendritic cells incubated with P. gingivalis that express native hemagglutinin B, and also to assess the ability of this AP to reduce hemagglutinin B-induced inflammation in animal models of periodontal disease.