ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Role of Microenvironment in Pathological Inflammation (#255)

Svetlana Shatunova 1 , Hana Starobova 2 , Kristen Radford 1 , Ingrid Winkler 1
  1. Faculty of Medicine, Mater Research Institute-UQ, The University of Queensland, Brisbane, Queensland, Australia
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

Vascular homing adhesion molecules such selectins and integrin ligands expressed by endothelial cells (ECs) are part of immune cell microenvironment. Vascular adhesion molecules are more highly expressed on damaged or activated vascular playing an important role in recruitment of leukocytes to the site of infection/injury via direct contact with immune cell (1-3) . Our hypothesis is these immune cell adhesion molecules may play additional roles in immune cell priming as well.

Deletion of E-selectin and P-selectin in gene-deleted mice decreases leukocyte recruitment to the sites of inflammation. P-selectin is most important for this role while endothelial (E)-selectin almost redundant for leukocyte homing (1).

Instead our studies demonstrate E-selectin to be active microenvironmental factor involved in the regulation of haematopoietic stem cell self-renewal (3) as well as activation of cultured bone marrow derived macrophages (4) especially in regards to boosting  chemokine CCL2 release which may attract other leukocytes (5). Interestingly we also find therapeutic blockade of E-selectin in mice dampens the release of pro-inflammatory cytokines in response to growth factor administration (6) suggesting a potentially important role for endothelial E-selectin in modulating the immune cell microenvironment. In particular playing role in the amplification of pathological immune responses.

Using freshly isolated human CD14+ blood monocytes we further find adhesive interactions with E-selectin are unique in promoting enhanced release of pro-inflammatory cytokines TNF-α, IL-6 and chemokines CCL2 and IL-8 in culture and furthermore strongly synergise with bacterially derived endotoxin (LPS) a pathogen-associated molecular pattern (PAMP).

Together our findings suggest vascular leukocyte homing molecules play important additional roles distinct from their well-known role in immune cell recruitment, especially in the regulation or fine-tuning of monocyte activation. These ongoing studies may lead to improved strategies to dampen acute pathological inflammation and chronic inflammation of ageing.

  1. Frenette PS, Wagner DD. Insights into selectin function from knockout mice. Thromb Haemost. 1997;78(1):60-4
  2. Darveau RP, Pham TT, Lemley K, Reife RA, Bainbridge BW, Coats SR, et al. Porphyromonas gingivalis lipopolysaccharide contains multiple lipid A species that functionally interact with both toll-like receptors 2 and 4. Infection and immunity. 2004;72(9):5041-51.
  3. Baines PB, Marzouk O, Thomson AP, Sills JA, Riordan FA, Hart CA. Endothelial cell adhesion molecules in meningococcal disease. Arch Dis Child. 1999;80(1):74-6.
  4. Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT, et al. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nature medicine. 2012;18(11):1651-7.
  5. Davies JM, Radford KJ, Begun J, Levesque JP, Winkler IG. Adhesion to E-selectin primes macrophages for activation through AKT and mTOR. Immunology and cell biology. 2021;99(6):622-39.
  6. Magnani JL, Fogler WE, Winkler IG (inventors), Patent: Selectin or gelectin antagonists for treating cytokine release syndrome and CRS-induced neurotoxicity. 2020. Int Patent Number WO-2020150263-A1