Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Lung macrophage heterogeneity as a translatable avenue for human immunophenotyping (#45)

Mubing Duan 1 2 3 , Daniel P Steinfort 4 , David Smallwood 4 , Mark Hew 5 , Matthias Ernst 6 , Louis B Irving 4 , Gary P Anderson 7 , Margaret Hibbs 2
  1. Biochemistry, La Trobe University, Bundoora, VIC, Australia
  2. Immunology, Monash, AMREP, VIC, Australia
  3. Surgery, University of Melbourne, Parkville, VIC, Australia
  4. Respiratory Medicine, Royal Melbourne Hospital, Parkville, VIC, Australia
  5. Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Prahran, VIC, Australia
  6. The Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, Australia
  7. Pharmacology, University of Melbourne, Parkville, VIC, Australia

Macrophages underlie the pathological processes of many acute and chronic diseases, yet no translatable panels currently exist for their study in human patients. A major challenge has been in the identification of selective and translatable markers of cell activation as many M1/M2 macrophage markers are absent or differentially expressed in human patients. This is particularly true for alveolar macrophages (AMΦs), which predominate within the alveolar airspaces and influence both tissue homeostasis and lung disease pathogenesis.

We show that Mac-1 expression is a novel and translatable marker of residential AMΦ heterogeneity in both humans and mice. Human patients exhibited a naturally heterogeneous distribution of AMΦ Mac-1 expression. Patients with Mac-1low AMΦs shared a similar lung immunophenotype with healthy C57BL/6 mice whereas patients with Mac-1high AMΦs or Mac-1mod/high AMΦs with infiltrating eosinophils mirrored the immunophenotypes of SHIP-1-/- or HckF/F mice which develop features of human COPD. Heightened AMΦ Mac-1 upregulation was further identified as a feature of acute lung exacerbations in SHIP-1-/- and HckF/F. Selective targeting of Mac-1high but not Mac-1low/neg AMΦs attenuated LPS-induced lung inflammation in C57BL/6 mice and decreased the severity of acute lung exacerbations in treatment-responsive SHIP-1-/- mice. Altogether, our data demonstrates that Mac-1 is an important and translatable marker of AMΦ heterogeneity, and highlights the possibility of lung macrophage profiling in identifying distinct inflammatory phenotypes in mouse and human lungs.