Cecilia Hagert

University of Turku,
Supervisor: Rikhard Holmdahl, Sirpa Jalkanen
Funding: ISB
Date: 2012-01-01

Macrophage regulation of inflammation through reactive oxidative species

Background: Rheumatoid Arthritis (RA) affects about 1% of the population in Europe. It is a chronic inflammatory disease affecting mainly the peripheral joints. The inflammation leads to cartilage destruction, bone erosion and joint deformation, which make RA a disabling disease. Several genes and environmental factors contribute to cause the disease. There is currently no cure to RA, although progress has been made based on the identification of the TNF-α pathway. The hope is to be able to predict the disease development, through genetic and immune markers, and treat the disease by interacting with the relevant disease-associated pathways.

So far it has been difficult to identify the most relevant genes due to the complexity of the disease. In experimental models for RA, two genes have so far been conclusively positioned. One is the MHC class II gene Aq, which corresponds well with the human DR alleles associated with RA. The other is Ncf1, a conserved gene which is polymorphic in the rat and has been positionally cloned as a major gene controlling arthritis severity (Olofsson, Nat Gen 2003). A mutation in the Ncf1 gene in the mouse confirmed the importance of this gene and shows that it is associated with an evolutionary conserved molecular pathway, likely to operate also in humans (Hultqvist PNAS 2004, Gelderman PNAS 2006, Gelderman JCI 2007). Furthermore, Ncf1 allele leading to lower oxidative burst was associated with more severe arthritis. The prime cell populations regulating this effect are CD68+ macrophages.

The rational for a redox regulatory effect by macrophages could be to down-regulate an ongoing acute inflammation, to prevent this to develop into a chronic, autoimmune and pathogenic scenario. Both innate and T cell dependent pathways might operate to protect against chronic inflammation, it remains to understand in detail how these pathways operate and how they can be therapeutically utilized.

Aim: To identify molecular downstream oxidation pathways by which macrophages regulate inflammation.

Methods: Using a series of genetically modified mouse strains, including strains with transgenic and conditional induction of Ncf1 on macrophages, the regulation of different macrophage subpopulations will be investigated. Furthermore, mouse strains deficient of selected C type lectins like the mannose receptor (MR) will be used. The mouse strains will be tested in selected arthritis models, which operate through different pathways, for example mannan-induced arthritis, collagen induced arthritis (CIA) and collagen antibody induced arthritis (CAIA). Identification of these new pathways may reveal new therapeutic targets for treatment of RA and other inflammatory diseases.