The effect of age on complement activation and monocyte-derived complement responses in primary human immune cells

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. This clinical syndrome is characterised by two seemingly opposing responses manifesting simultaneously, that is sustained excessive inflammation, and immunosuppression that leaves the host susceptible to secondary infections. Older age is a strong risk factor for severe sepsis, with the elderly population having an increased sepsis-associated mortality rate. This could be partly attributed to age-associated immune compromise, a phenomenon known as immunosenescence, which also effects complement system activation, the focus of this study. The Complement system plays a critical role in the innate immune response, from opsonization, pattern recognition to propagation of inflammation. Dysregulation of the Complement system has been implicated in several diseases, albeit limited in the context of ageing processes. The central hypothesis of this study was that systemic ageing is characterized by aberrant complement activation, and that monocytes are capable of producing complement factors. To test this hypothesis, the study combined immunological, cell biological, and bioinformatic methodologies. Plasma biomarker measurements were performed in an age-discordant cohort of human participants, using plasma samples to quantify the complement factors C5a and C2. C2 was found at significantly higher levels in elderly donors (n = 21; >65 years) compared with young donors (n = 19; 18–30 years), C5a was not found to be significantly higher. Monocytes isolated from a subset of participants were subsequently used to assess the inducibility of complement factor C2. Upon stimulation with lipopolysaccharide (LPS), monocytes exhibited only minimal C2 and C9 production, however this production was not statistically significant. To further explore complement production by monocytes and monocyte-derived macrophages, publicly available datasets were interrogated for the inducibility of complement-related genes. These bioinformatic analyses demonstrated significant changes in the expression of complement components, particularly early classical/lectin pathway components and complement regulatory genes, following LPS stimulation and adherence. Collectively, these findings support the concept that ageing is associated with altered complement regulation, and that, monocytes and monocyte-derived macrophages can transcribe and secrete complement.