Back to search

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Decoding the intracellular complement system in inflammatory reactions

Alternative title: Betydningen av intracellulært komplement for kontroll av inflammasjonsresponser

Awarded: NOK 9.6 mill.

The liver-derived and plasma-circulating complement system is a key member of the host’s repertoire of pathogen- and damage-associated molecular pattern (PAMP and DAMP) sensors. Pathogen sensing in blood triggers activation of complement component 3 into C3a and C3b and of C5 into C5a and C5b, by C3 and C5 convertases, respectively. This complement activation mediates the opsonization and removal of invading microbes, mobilization of immune cells, and induction of a general inflammatory reaction. Recent work has led to the unexpected discovery of an intracellularly active complement system, termed the complosome. We have recently shown that macrophages have an intracellular C5 system and recruit intracellular C5a receptor 1 (C5aR1) for inflammatory responses after sensing of danger signals. Unexpectedly, C5aR1 mediates these inflammatory effects by interacting with C5a on the mitochondria. Our findings raise several new and important questions that need to be addressed. The project will explore intracellular trafficking mechanisms of C5a and C5aR1 that control mitochondrial production of reactive oxygen species and inflammasome activation. We aim to find the signalling mechanisms used by C5aR1 on mitochondria, and the role of intracellular complement in bacteria-induced killing of macrophages. It will also be examined if the intracellular C5 system controls immune sensing of cytosolic DNA and RNA that can be released from virus and damaged mitochondria. Obtained results will have high general relevance and potential as it provides novel insight into mechanisms of how macrophages respond to sterile and infectious danger.

The liver-derived and plasma-circulating complement system is a key member of the host’s repertoire of pathogen- and damage-associated molecular pattern (PAMP and DAMP) sensors. Pathogen sensing in blood triggers activation of C3 (complement component 3) into C3a and C3b and of C5 into C5a and C5b, by C3 and C5 convertases, respectively. These complement activation fragments together mediate the opsonization and removal of invading microbes, mobilization of immune cells, and induction of a general inflammatory reaction. Recent work has led to the unexpected discovery of a cell-autonomous, intracellularly active complement system, termed the complosome. We have just recently shown that macrophages have an intracellular C5 system and recruit intracellular C5a receptor 1 (C5aR1) for inflammatory responses after sensing of danger signals. Unexpectedly, C5aR1 mediates these inflammatory effects by interacting with C5a on the mitochondria. Our findings raise several new and important questions that need to be addressed. The project will explore intracellular trafficking mechanisms of C5a and C5aR1 that control mitochondrial reactive oxygen species production and inflammasome activation. We aim to find the signalling mechanisms used by C5aR1 on mitochondria, and the role of intracellular complement in bacteria-induced killing of macrophages. It will also be examined if the intracellular C5 system controls cytosolic immune sensing of DNA and RNA. Obtained results will have high general relevance and potential as it provides novel insight into mechanisms of how macrophages respond to sterile and infectious danger.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Funding Sources