Soluble mucus component CLCA1 modulates expression of leukotactic cytokines and BPIFA1 in murine alveolar macrophages but not in bone marrow-derived macrophages

Histochem Cell Biol. 2018 Jun;149(6):619-633. doi: 10.1007/s00418-018-1664-y. Epub 2018 Apr 2.


The secreted airway mucus cell protein chloride channel regulator, calcium-activated 1, CLCA1, plays a role in inflammatory respiratory diseases via as yet unidentified pathways. For example, deficiency of CLCA1 in a mouse model of acute pneumonia resulted in reduced cytokine expression with less leukocyte recruitment and the human CLCA1 was shown to be capable of activating macrophages in vitro. Translation of experimental data between human and mouse models has proven problematic due to several CLCA species-specific differences. We therefore characterized activation of macrophages by CLCA1 in detail in solely murine ex vivo and in vitro models. Only alveolar but not bone marrow-derived macrophages freshly isolated from C57BL6/J mice increased their expression levels of several pro-inflammatory and leukotactic cytokines upon CLCA1 stimulation. Among the most strongly regulated genes, we identified the host-protective and immunomodulatory airway mucus component BPIFA1, previously unknown to be expressed by airway macrophages. Furthermore, evidence from an in vivo Staphylococcus aureus pneumonia mouse model suggests that CLCA1 may also modify BPIFA1 expression in airway epithelial cells. Our data underscore and specify the role of mouse CLCA1 in inflammatory airway disease to activate airway macrophages. In addition to its ability to upregulate cytokine expression which explains previous observations in the Clca1-deficient S. aureus pneumonia mouse model, modulation of BPIFA1 expression expands the role of CLCA1 in airway disease to involvement in more complex downstream pathways, possibly including liquid homeostasis, airway protection, and antimicrobial defense.

Keywords: Animal model; Gob-5; Pneumonia; SPLUNC; Translatability; mCLCA3.

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism*
  • Cell Differentiation
  • Cells, Cultured
  • Chloride Channels / deficiency
  • Chloride Channels / metabolism*
  • Cytokines / genetics*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Glycoproteins / genetics*
  • Glycoproteins / metabolism
  • Leukocytes / metabolism*
  • Leukocytes / pathology
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Solubility


  • Bpifa1 protein, mouse
  • Chloride Channels
  • Clca3a1 protein, mouse
  • Cytokines
  • Glycoproteins
  • Phosphoproteins