Abstract
Mammalian species contain an internal circadian (i.e., 24-h) clock that is synchronized to the day and night cycles. Large epidemiological studies, which are supported by carefully controlled studies in numerous species, support the idea that chronic disruption of our circadian cycles results in a number of health issues, including obesity and diabetes, defective immune response, and cancer. Here we focus specifically on the role of the complement immune system and its relationship to the internal circadian clock system. While still an incompletely understood area, there is evidence that dysregulated proinflammatory cytokines, complement factors, and oxidative stress can be induced by circadian disruption and that these may feed back into the oscillator at the level of circadian gene regulation. Such a feedback cycle may contribute to impaired host immune response against pathogenic insults. The complement immune system including its activated anaphylatoxins, C3a and C5a, not only facilitate innate and adaptive immune response in chemotaxis and phagocytosis, but they can also amplify chronic inflammation in the host organism. Consequent development of autoimmune disorders, and metabolic diseases associated with additional environmental insults that activate complement can in severe cases, lead to accelerated tissue dysfunction, fibrosis, and ultimately organ failure. Because several promising complement-targeted therapeutics to block uncontrolled complement activation and treat autoimmune diseases are in various phases of clinical trials, understanding fully the circadian properties of the complement system, and the reciprocal regulation by these two systems could greatly improve patient treatment in the long term.
Highlights
Circadian rhythms, oscillations of ∼24-h periodicity, are critical for a healthy immune system
Oscillations of ∼24-h periodicity, are critical for a healthy immune system. Both innate and adaptive immunity are regulated by the circadian clock at the level of the circadian pacemaker, the suprachiasmatic network (SCN), as well as by peripheral clocks in other tissues (Laste et al, 2013; Perfilyeva et al, 2017)
Circadian Clock and Complement Immunity information transmitted through the retinal ganglion cells (Ruby et al, 2002; Lucas et al, 2014)
Summary
Oscillations of ∼24-h periodicity, are critical for a healthy immune system. In particular factor H interacts with C3b on the host cell membranes and destabilizes C3 convertase and facilitates cleavage of C3b to inactive C3b (iC3b) and C3dg fragments; C3dg further gets cleaved into C3d, which helps in lowering the levels of circulating immune complexes (CIC), thereby limiting alternate complement pathway activation and keeping chronic inflammation in control (Petersen et al, 1985, 1986; Dorval et al, 1989; Kashyap et al, 1992; Sanchez-Cuenca, 1994) Autoimmune conditions, such as SLE tend to dysregulate the balance of degradation of immune complexes which results in decreased C3d-mediated complex releasing activity and increased levels of CICs (Sakurai et al, 1982). Both genetic and environmental disruption of the circadian clock system reveals previously unappreciated links between the circadian and complement systems
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