The Emerging Roles of Extracellular Chaperones in Complement Regulation

The immune system is essential to protect organisms from internal and external threats. The rapidly acting, non-specific innate immune system includes complement, which initiates an inflammatory cascade and can form pores in the membranes of target cells to induce cell lysis. Regulation of protein homeostasis (proteostasis) is essential for normal cellular and organismal function, and has been implicated in processes controlling immunity and infection. Chaperones are key players in maintaining proteostasis in both the intra- and extracellular environments. Whilst intracellular proteostasis is well-characterised, the role of constitutively secreted extracellular chaperones (ECs) is less well understood. ECs may interact with invading pathogens, and elements of the subsequent immune response, including the complement pathway. Both ECs and complement can influence the progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, as well as other diseases including kidney diseases and diabetes. This review will examine known and recently discovered ECs, and their roles in immunity, with a specific focus on the complement pathway.