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Women and Inflammation

Research group
Active research
Project owner
Sahlgrenska Academy, Institute of Medicine, Department of Rheumatology and Inflammation Research

Financier
Swedish Research Council, Novo Nordisk Foundation, ALF VG-region, Swedish Society of Rheumatism, Professor Nanna Swartz foundation, IngaBritt & Arne Lundberg foundation, Marie Sklodowska-Curie Action, Gustaf V 80-year foundation, Cornells foundation

Short description

Sex hormones have major effects on the immune system, which greatly influences the risk of developing certain diseases. For example there is a clear female bias in the development of both autoimmune diseases and asthma. The research group studies how the female sex hormone estrogen affect immune responses during inflammatory diseases caused by autoimmunity, allergy or infections.

Our research

The projects focus, among others, on determining whether the effects of estrogen on development, activation and function of the immune system during autoimmune diseases and associated osteoporosis are mediated by stromal cells in primary and secondary lymphoid organs. Another focus area is to define the mechanisms involved in the effects of estrogen on immune responses during infection- and allergy-induced airway inflammation. The projects range from basic research (in vitro and in vivo), to clinical studies in collaboration with medical doctors at the Sahlgrenska University hospital.

Main research projects

Effects of estrogen on the immune system in autoimmune diseases and associated osteoporosis
Rheumatoid arthritis (RA) is a chronic autoimmune disease resulting in joint inflammation and development of osteoporosis. Women have increased risk of developing RA compared to men, and the peak incidence coincides with the time of menopause when the levels of estrogen rapidly decrease. Systemic Lupus Erythematosus (SLE) is an autoimmune disease, which to app. 90% affects women and essentially can affect all organs in the body. The disease often debuts during the reproductive age when the levels of estrogen are high and women with SLE have an increased to develop osteoporosis. Estrogen inhibits RA but worsens SLE, while it protects against osteoporosis in both diseases. The three-dimensional structure of lymphoid organs is made by stromal cells, but stromal cells also have major effects on the activation and function of immune cells. The mechanisms underlying the opposing effects of estrogen in RA and SLE are unclear and defining them would provide opportunities to develop new and better therapies for many inflammatory conditions that are affected by estrogen. The aims of this project are to; (1) identify the mechanisms underlying the opposing effects of estrogen on immune responses in RA and SLE, and to (2) define whether the protective effects of estrogen on osteoporosis development in RA and SLE are mediated by bone marrow stromal cells.

Group members working in this project:

Intracellular interactions between estrogen- and adenosine-signaling in osteoarthritis
Osteoarthritis (OA) is a chronic disabling disease where the joint cartilage is destroyed, leading to pain and loss of joint function. During recent years, the importance of inflammation in OA pathogenesis has gained attention, but the specific mechanisms involved in the disease initiation and progression needs to be clarified. Women have an increased risk of developing OA compared to men, and the risk increases at the time of menopause when the levels of estrogen decreases. Epidemiological studies also suggest that estrogen may play an important role in OA disease development. Adenosine is an endogenously produced molecule that can exert both pro- and anti-inflammatory effects in the joints, regulated by signaling through different adenosine receptors. It has been shown that mice lacking adenosine receptor A2A spontaneously develop OA, with milder disease symptoms in female compared to male mice. Interestingly, estrogen can modulate the cellular expression of adenosine receptors. The aims of this project are to; (1) determine how estrogen- and adenosine-signaling interact in immune cells during OA development, and to (2) define how these intracellular signaling pathways can be targeted for development of new OA therapies.

Group member working in this project:

  • Carmen Corciulo, PhD - EU researcher (Marie Sklodowska Curie Individual Fellow)

Effects of estrogen on immune responses during airway inflammation
Sex hormones affect the development and function of the immune system, which can be illustrated by a stronger immune response in females towards e.g., influenza virus infection, and by the increased risk for women in the fertile age to develop asthma. The specific mechanisms underlying the sex differences in immune responses during airway inflammation is not clear. However, it is well known that estrogen can display either stimulatory or inhibitory effects on different parts of the immune system depending on the settings. For example, estrogen stimulates the secretion of antibodies from B cells but decreases the production of different pro-inflammatory cytokines. The aims of this project are to; (1) identify the mechanisms involved in the effects of estrogen on immune responses during allergen- and virus-induced airway inflammation, and to (2) determine the importance of stromal cells in primary and secondary lymphoid organs for the estrogen-mediated regulation of immune responses.

Group members working in this project:

  • Scheffler JM, Gustafsson KL, Barrett A, Corciulo C, Drevinge C, Del Carpio Pons AM, Humeniuk P, Engdahl C, Gustafsson J-Å, Ohlsson C, Carlsten H, Lagerquist MK, Islander U 
    ERa signaling in a subset ofCXCL12-abundant reticular cells regulates trabecular bone in mice
    JBMR plus. 2022 May DOI: 10.1002/jbm4.10657
     
  • Nordqvist J, Engdahl C, Scheffler JM, Gupta P, Gustafsson KL, Lagerquist MK, Carlsten H, Islander U
    A tissue-selective estrogen complex as treatment of osteoporosis in experimental lupus 
    Lupus. 2022 Feb;31(2):143-154.
     
  • Drevinge C, Scheffler JM, Karo-Arvidsson C, Sundh D, Carlsten H, Gjertsson I, Lindholm C, Lorentzon M, Rudin A, Hultgard-Ekwall AK, Islander U
    Intermediate monocytes correlate with CXCR3+ Th17 cells but not with bone characteristics in untreated early rheumatoid arthritis
    PLoS One. 2021 Mar 26;16(3)
     
  • Scheffler JM, Grahnemo L, Engdahl C, Drevinge C, Gustafsson KL, Corciulo C, Lawenius L, Iwakura Y, Sjögren K, Lagerqvist MK, Carlsten H, Ohlsson C, Islander U 
    Interleukin-17A: a Janus-faced regulator of osteoporosis
    Sci Rep. 2020 Mar 30;10(1):5692.
     
  • Perez-Shibayama C, Islander U, Lütge M, Cheng HW, Onder L, Ring S, de Martin A, Novkovic M, Colston J, Gil-Cruz C, Ludewig B
    Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8+ T cells
    Sci Immunol. 2020 Sep 11;5(51)