Novel mechanisms and functions of complement

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Abstract

<p class="first" id="P1">Progress in the beginning of the 21 <sup>st</sup> century transformed our perception of complement from a blood-based antimicrobial system to a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances regarding structure-function insights, mechanisms and locations of complement activation, thereby adding new layers of complexity in the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer. This Review provides an updated view of new and previously unanticipated functions of complement and how these impact immunity and disease pathogenesis. </p>

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Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response.

George Hajishengallis (2014)

Recent studies have uncovered novel mechanisms underlying the breakdown of periodontal host-microbe homeostasis, which can precipitate dysbiosis and periodontitis in susceptible hosts. Dysbiotic microbial communities of keystone pathogens and pathobionts are thought to exhibit synergistic virulence whereby not only can they endure the host response but can also thrive by exploiting tissue-destructive inflammation, which fuels a self-feeding cycle of escalating dysbiosis and inflammatory bone loss, potentially leading to tooth loss and systemic complications. Here, I discuss new paradigms in our understanding of periodontitis, which may shed light into other polymicrobial inflammatory disorders. In addition, I highlight gaps in knowledge required for an integrated picture of the interplay between microbes and innate and adaptive immune elements that initiate and propagate chronic periodontal inflammation.

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Augmented Wnt signaling in a mammalian model of accelerated aging.

Hongjun Liu, Maria Fergusson, Rogerio M. Castilho … (2007)

The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.

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T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells

G. Arbore, E. E. West, R. Spolski … (2016)

The NLRP3 inflammasome controls interleukin-1β maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4(+) T cells and initiates caspase-1-dependent interleukin-1β secretion, thereby promoting interferon-γ production and T helper 1 (T(H)1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2. Aberrant NLRP3 activity in T cells affects inflammatory responses in human autoinflammatory disease and in mouse models of inflammation and infection. Our results demonstrate that NLRP3 inflammasome activity is not confined to "innate immune cells" but is an integral component of normal adaptive T(H)1 responses.

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Author and article information

Journal

Title: Nature Immunology

Abbreviated Title: Nat Immunol

Publisher: Springer Nature

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Created: November 16 2017

Publication date (Print): November 16 2017

Volume: 18

Issue: 12

Pages: 1288-1298

Article

DOI: 10.1038/ni.3858

PMC ID: 5706779

PubMed ID: 29144501

SO-VID: f1b9d8b2-6f34-4037-a9d5-db14b7f18288

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Novel mechanisms and functions of complement

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Coronaviruses, COVID-19 and SARS-CoV-2

Most cited references 83

Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response.

Augmented Wnt signaling in a mammalian model of accelerated aging.

T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells

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