Circadian Clock and Complement Immune System—Complementary Control of Physiology and Pathology?

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.

Clocks, Viruses, and Immunity: Lessons for the COVID-19 Pandemic

“…This article summarizes the findings and key action points that emerged from this multidisciplinary discussion on the interface of circadian biology and immunity. While there are many excellent reviews on circadian biology and immunity ( Mavroudis et al, 2013 ; Scheiermann et al, 2013 ; Butler and Gibbs, 2020 ; Nosal et al, 2020 ; Shivshankar et al, 2020 ), our aim is to review the literature that is directly pertinent to SARS-CoV-2 and COVID-19 pathology. Furthermore, we speculate on the translational aspects of chronobiology that may impact this pandemic.…”

Soluble Membrane Attack Complex: Biochemistry and Immunobiology

“…Complement-mediated immune effector functions include chemoattraction of immune cells, activation of leukocytes, platelets and essentially all cell types proximal to complement activation, opsonization of invading pathogens, enhancement of the acutephase response, lysis of susceptible pathogens and modulation of lymphocyte-mediated immune responses (1,2,(4)(5)(6). Complement also serves to help in controlling T and B cell activation and function, stem cells and developmental processes, modulate basic cellular processes in intracellular sensing and cellular metabolism as it relates to immune responses (7)(8)(9)(10)(11)(12)(13)(14)(15), synaptic pruning (16,17), modulation of the circadian clock (18), and possible contributions to schizophrenia (19,20). Effector functions mediated by complement are driven by the proteolytic generation of activation fragments that either 1) bind to receptors expressed on both immune and non-immune cells, or 2) covalently attach to cell surfaces adjacent to sites of complement activation (1-3).…”

Proteome profile of patients with excellent and poor speech intelligibility after cochlear implantation: Can perilymph proteins predict performance?

“…Another factor found in the perilymph of patients that later were shown to become excellent performer with their implant is complement C8, an important antibacterial immune effector [ 35 ]. Complement C8 initiates membrane penetration and coordinates membrane attack complex (MAC) pore formation leading to cell lysis [ 35 ]. It has close interaction with other complement types e.g., C6, C7, C9.…”