More than complementing Tolls: complement–Toll‐like receptor synergy and crosstalk in innate immunity and inflammation

Abstract

Summary Complement and Toll-like receptors (TLRs) play key roles in the host immune response and are swiftly activated by infection or other types of immunological stress. This review focuses on the capacity of complement and TLRs to engage in signaling crosstalk, ostensibly to coordinate immune and inflammatory responses through synergistic or antagonistic (regulatory) interactions. However, over-activation or dysregulation of either system may lead – often synergistically – to exaggerated inflammation and host tissue injury. Intriguingly, moreover, certain pathogens can manipulate complement-TLR crosstalk pathways in ways that undermine host immunity and favor their persistence. In the setting of polymicrobial inflammatory disease, subversion of complement-TLR crosstalk by keystone pathogens can promote dysbiosis. Knowledge of the molecular mechanisms underlying complement-TLR crosstalk pathways can, therefore, be used productively for tailored therapeutic approaches, such as, to enhance host immunity, mitigate destructive inflammation, or counteract microbial subversion of the host response.

Novel mechanisms and functions of complement

“…Differences in the outcomes of C3-dependent opsonophagocytosis might be attributed to several experimental variables, including the type of organisms, the use of non-immune cells vs. professional phagocytes, or the identity of complement receptors mediating pathogen entry. When bacterial pathogens enter macrophages via complement receptor-3 (CR3) ( e.g ., P. gingivalis , Francisella tularensis , and Bacillus anthracis spores), they enhance their intracellular persistence and capacity to cause disease in the mouse host 8 (Fig.2, right). The underlying mechanism was described in detail for F. tularensis , a facultative intracellular bacterium that can escape from the phagosome to replicate within the cytosol.…”

“…Complement components can be secreted locally by tissue-resident and infiltrating cells, while emerging evidence suggests the existence of an intracellular complement system with novel homeostatic and immune functions 2 . New insights into the mechanisms and locations of complement activation have revealed a new layer of complexity in the biology of complement and its impact on health and disease 7,8 . When dysregulated or overactivated due to host genetic or microbial virulence factors, complement can turn from a homeostatic to a pathological effector that drives various inflammatory disorders and cancer, which reflect the multifaceted nature of complement interactions 3,9 .…”

Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion

“…Moreover, cross-talk between the complement system and TLRs is essential to obtain an optimal response against the invading microbes. Finally, intracellular complement activation in T-cells is important for the regulation of the adaptive immune response (reviewed Freeley et al, 2016; Hajishengallis and Lambris, 2016). The complement system is the first line of defense against invading microbes.…”

Environmental lead effects on gene expression in oral epithelial cells

“…CD59 is also involved in complement‐mediated immune reactions and the LPS from T. denticola and T. forsythia upregulated surface expression of various complement regulatory proteins, including CD59, in oral epithelial cells . An array of recent findings has actively implicated the complement system as a critical component of innate immunity in periodontitis . CD70 is a cytokine that belongs to the TNF ligand family and is decreased in oral epithelial cells stimulated with oral bacteria or LPS .…”