Macrophage immunomodulation in chronic osteolytic diseases-the case of periodontitis

Abstract

Periodontitis (PD) is a chronic osteolytic disease that shares pathogenic inflammatory features with other conditions associated with nonresolving inflammation. A hallmark of PD is inflammation-mediated alveolar bone loss. Myeloid cells, in particular polymorphonuclear neutrophils (PMN) and macrophages (Mac), are essential players in PD by control of gingival biofilm pathogenicity, activation of adaptive immunity, as well as nonresolving inflammation and collateral tissue damage. Despite mounting evidence of significant innate immune implications to PD progression and healing after therapy, myeloid cell markers and targets for immune modulation have not been validated for clinical use. The remarkable plasticity of monocytes/Mac in response to local activation factors enables these cells to play central roles in inflammation and restoration of tissue homeostasis and provides opportunities for biomarker and therapeutic target discovery for management of chronic inflammatory conditions, including osteolytic diseases such as PD and arthritis. Along a wide spectrum of activation states ranging from proinflammatory to pro-resolving, Macs respond to environmental changes in a site-specific manner in virtually all tissues. This review summarizes the existing evidence on Mac immunomodulation therapies for osteolytic diseases in the broader context of conditions associated with nonresolving inflammation, and discusses osteoimmune implications of Macs in PD.

Keywords: bone; macrophage; osteoimmunology; osteolysis.

FIGURE 1. Overview of the effector cells in the pathogenesis of periodontitis.

In early lesions, bacterial antigens from putative pathogenic bacteria found in the subgingival biofilm activate dendritic cells and tissue resident macrophages, and stimulate recruitment of natural killer cells, T cells, and polymorphonuclear neutrophils (PMN). Antigens are processed and presented to local cells by macrophages, dendritic cells, PMN and lymphocytes. Dendritic cells, macrophages, and B cells are the principal antigen-presenting cells for T cells, whereas follicular dendritic cells are the main antigen-presenting cells for B cells. Inflammatory macrophage (iMac) and neutrophils up-regulate production of proinflammatory mediators, reactive oxygen/nitrogen species, and metalloproteases, which promote extracellular matrix degradation and osteoclastic activity. Resolving macrophages (rMac) mediate inflammation resolution by increasing phagocytosis of dying cells (PMNs and others), clearance of proinflammatory signals, and tissue regeneration likely, in part, through promotion of otesoblastic activity. The imbalance between osteoblast and osteoclast activities is believed to be caused by bacterial products and inflammatory cytokines, and constitutes an important pathologic axis underlying inflammation-mediated bone loss

FIGURE 2. Periodontal Osteoimmunology.

Nonresolving periodontal inflammation is characterized by a proinflammatory loop sustained by neutrophils and inflammatory monocytes/macrophages (iMo/iMac). Resident macrophages and classical dendritic cells act as professional antigen presenting cells that initiate inflammation when bacterial antigens enter the tissues. IFN-γ and LPS activate iMac. Persistence of chemoattractants for neutrophils (fMLP, IL-8, LTB₄) and inflammatory monocytes (CCL2) results in maintenance of an inflammatory niche dominated by macrophage derived cytokines IL-1β, IL-8, IL-12, IL-23, TNF-α, and MMPs, which in turn activate Th cells (Th17 and Th1) to produce IL-8, IL-17, and RANKL. This in turn promotes neutrophil recruitment, and differentiation and activation of osteoclasts via MCSF-RANKL. High tissue levels of CCL2 also recruits osteoclast precursors on the bone surface. In nonsusceptible individuals, efficient control of biofilm composition by innate immune cells and disruption of maturing sub gingival biofilms results in active resolution of inflammation coordinated cellularly by resolving macrophages (rMac), and molecularly by SPMs (lipoxins and resolvins) and anti-inflammatory factors IL-1RA, IL-4, IL-10, IL-13, IGF-1, TGF-β, TIMPs, and OPG. This is likely supported by recruitment of patrolling monocytes (pMo) via CX₃CL1, B/plasma cell and Th2 derived cytokines, and osteomacs in the canopy structures surrounding osteoblasts. IL-1RA, TIMPs, and OPG directly block major proinflammatory and osteoclast stimulation pathways. Abbreviations: OB, osteoblast, OC, osteoclast; Th, T helper CD4+ lymphocyte; fMLP, formylmethionyl-leucyl-phenylalanine; IL-1RA, IL-1 receptor antagonist; MMP, matrix metalloproteases; TIMP, tissue inhibitors of MMPs

FIGURE 3. Monocyte (Mo) and Macrophage (Mac) Immune Modulation.

Bone marrow and spleen release classical Mo have inflammatory properties, termed “inflammatory” Mo (iMo) as well as nonclassical Mo that display patrolling properties and are termed “patrolling” Mo (pMo). The short-lived iMo become pMo with extended life span by shedding CCR2 and up-regulating CX₃CR1. pMo that recruit into tissues are thought to generate resolving Mac (rMac) that maintain tissue homeostasis. Importantly, at sites of inflammation, upon stimulus neutralization inflammatory Mac (iMac) switch their metabolism to perform pro-healing/regeneration functions, thus becoming rMac. Therefore, depending on local signals Mac perform complementary functions: iMac coordinate pathogen neutralization whereas rMac coordinate tissue clearance through increased efferocytosis. These actions regulate adaptive immunity mediated by B and T lymphocytes, and restoration of tissue homeostasis by clearance through lymphatics. Mac inhibition by clodronate targets all Mac, whereas Linomide and APDs inhibit iMac by blocking the IFN-γ pathway and the LPS-induced release of iMac activating factors. iMo-to-pMo and iMac-to-rMac conversion is enhanced by specialized pro-resolving mediators (SPMs) and TZDs, IL-4 and IL-10, glucocorticoids and TGF-β