Research

The Fagerholm group studies the role of leukocyte integrins in various immune reactions.We are interested in the in vivo roles and regulation of leukocyte beta2-integrins in a healthy and dysfunctional immune system.

Integrin-mediated cell adhesion, migration and signalling is crucial for proper immune system function. Integrins regulate leukocyte functions such as lymphocyte recirculation, access of leukocytes into inflamed tissue, phagocytosis, immune cell signaling, T cell activation and effector functions. Investigations of the regulation of integrins are therefore fundamental for our understanding of immune system function in health and disease. In addition, integrins are recognized therapeutic targets in the intervention with human disease. Our group is interested in the in vivo roles and regulation of leukocyte beta2-integrins in a healthy and dysfunctional immune system.

Immune cells constantly traffic around the body, looking for infection. For example, immune cells such as neutrophils and T cells need to exit the blood stream and enter tissues to perform their functions, such as killing bacteria, virus-infected cells or tumor cells. The importance of beta2-integrins for immune responses is shown by the rare genetic disorders, leukocyte adhesion deficiency (LAD) type I and III, where integrin expression or function is lost. In LAD-III, integrins are normally expressed but do not function properly because an important cytoplasmic regulator of integrins, called kindlin-3, is mutated. Patients with these disorders suffer from recurrent bacterial infections because of deficient immune cell trafficking and function.

Our laboratory is interested in molecular mechanisms regulating immune cell trafficking in homeostasis and inflammation.  We have created a novel mouse model to investigate the role of the integrin regulator kindlin-3 in vivo. In the mouse model the integrin/kindlin link has been disrupted. We have shown that the integrin-kindlin link is necessary for immune cell adhesion and trafficking both in homeostasis and in skin inflammation, and also for optimal T cell activation in vivo. We are currently investigating the molecular mechanisms involved in integrin/kindlin-mediated regulation of immune cell adhesion. We are also investigating the role of other integrin regulators in immune cell trafficking and functions in vivo, using transgenic mouse models.

References

Morrison VL, MacPherson M, Savinko T, Lek HS, Prescott A, Fagerholm SC. The β2 integrin-kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo. Blood. 2013 Aug 22;122(8):1428-36. doi: 10.1182/blood-2013-02-484998. http://www.bloodjournal.org/content/122/8/1428

Morrison VL, Uotila LM, Llort Asens M, Savinko T, Fagerholm SC. Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function-Associated Antigen-1 and Kindlin-3. J Immunol. 2015 Jul 1;195(1):105-15. doi: 10.4049/jimmunol.1402741. http://www.jimmunol.org/content/195/1/105.full

Savinko TS, Morrison VL, Uotila LM, Wolff CH, Alenius HT, Fagerholm SC. Functional Beta2-Integrins Restrict Skin Inflammation In Vivo. J Invest Dermatol. 2015 Sep;135(9):2249-57. doi: 10.1038/jid.2015.164. http://www.jidonline.org/article/S0022-202X%2815%2939013-8/abstract

Dendritic cells are the main antigen presenting cells in the immune system, and play an important role in “kicking off” the immune response. Interestingly, our work has shown that integrins play a novel role in dendritic cells; these receptors restrict dendritic cell activation, programming of the dendritic cell to a migratory phenotype and migration from tissues to lymph nodes in vivo. As a result, when integrins in dendritic cells are nonfunctional, this leads to increased T cell activation in vivo. In addition, mice where beta2-integrins are dysfunctional display increased skin inflammation in vivo.

These results show that integrins play important immunoregulatory roles in vivo. We are currently investigating the molecular mechanisms involved in beta2-integrin-mediated immunomodulation, using transgenic mouse models and novel proteomic methods.

References

Morrison VL, James MJ, Grzes K, Cook P, Glass DG, Savinko T, Lek HS, Gawden-Bone C, Watts C, Millington OR, MacDonald AS, Fagerholm SC. Loss of beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype. Nat Commun. 2014 Oct 28;5:5359. doi: 10.1038/ncomms6359. http://www.nature.com/articles/ncomms6359

Savinko TS, Morrison VL, Uotila LM, Wolff CH, Alenius HT, Fagerholm SC. Functional Beta2-Integrins Restrict Skin Inflammation In Vivo. J Invest Dermatol. 2015 Sep;135(9):2249-57. doi: 10.1038/jid.2015.164. http://www.jidonline.org/article/S0022-202X%2815%2939013-8/abstract

Recently, a single nucleotide polymorphism conferring an amino acid change in the CD11b integrin chain extracellular domain, R77H, was shown to be associated with systemic lupus erythematosus, an autoimmune disease.

The CD11b/CD18 (Mac-1) integrin is expressed mainly on myeloid cells and binds several ligands. It is involved in essential immunological processes, such as leukocyte extravasation and phagocytosis. In addition, Mac-1 has been described to negatively regulate immune cell signaling. Our group was the first to show that the R77H-substituted Mac-1 is severely deficient in cell adhesion to ligands and in phagocytosis, and is also deficient in restricting cytokine responses in myeloid cells.

These deficiencies of integrin functions may ultimately lead to detrimental effects on the immune system (for example, problems in clearing immune complexes and/or apoptotic cells) and contribute to the development of systemic lupus erythematosus. We are interested in the molecular mechanisms underlying deficient R77H-Mac-1 functions in immune cells and in the immunological effects of lupus-associated integrin variants in vivo.

References
MacPherson M, Lek HS, Prescott A, Fagerholm SC. A systemic lupus erythematosus-associated R77H substitution in the CD11b chain of the Mac-1 integrin compromises leukocyte adhesion and phagocytosis.  J Biol Chem. 2011 May 13;286(19):17303-10. doi: 10.1074/jbc.M110.182998. http://www.jbc.org/content/286/19/17303.full

Fagerholm SC, MacPherson M, James MJ, Sevier-Guy C and Lau CS.  The CD11b-integrin (ITGAM) and systemic lupus erythematosus. Lupus (2013) 22, 657–663 http://lup.sagepub.com/content/22/7/657.full.pdf+html