Contribution of dipeptidyl peptidase 4 to non-typeable Haemophilus influenzae-induced lung inflammation in COPD

Clin Sci (Lond). 2021 Sep 17;135(17):2067-2083. doi: 10.1042/CS20210099.


Dipeptidyl peptidase 4 (DPP4) expression is increased in the lungs of chronic obstructive pulmonary disease (COPD). DPP4 is known to be associated with inflammation in various organs, including LPS-induced acute lung inflammation. Since non-typeable Haemophilus influenzae (NTHi) causes acute exacerbations in COPD patients, we examined the contribution of DPP4 in NTHi-induced lung inflammation in COPD. Pulmonary macrophages isolated from COPD patients showed higher expression of DPP4 than the macrophages isolated from normal subjects. In response to NTHi infection, COPD, but not normal macrophages show a further increase in the expression of DPP4. COPD macrophages also showed higher expression of IL-1β, and CCL3 responses to NTHi than normal, and treatment with DPP4 inhibitor, diprotin A attenuated this response. To examine the contribution of DPP4 in NTHi-induced lung inflammation, COPD mice were infected with NTHi, treated with diprotin A or PBS intraperitoneally, and examined for DPP4 expression, lung inflammation, and cytokine expression. Mice with COPD phenotype showed increased expression of DPP4, which increased further following NTHi infection. DPP4 expression was primarily observed in the infiltrated inflammatory cells. NTHi-infected COPD mice also showed sustained neutrophilic lung inflammation and expression of CCL3, and this was inhibited by DPP4 inhibitor. These observations indicate that enhanced expression of DPP4 in pulmonary macrophages may contribute to sustained lung inflammation in COPD following NTHi infection. Therefore, inhibition of DPP4 may reduce the severity of NTHi-induced lung inflammation in COPD.

Keywords: chronic obstructive pulmonary disease; exacerbations; macrophages; serine proteases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Case-Control Studies
  • Chemokine CCL20 / metabolism
  • Chemokine CCL3 / metabolism
  • Dipeptidyl Peptidase 4 / metabolism*
  • Disease Models, Animal
  • Female
  • Haemophilus Infections / enzymology*
  • Haemophilus Infections / microbiology
  • Haemophilus influenzae / pathogenicity*
  • Host-Pathogen Interactions
  • Humans
  • Interleukin-1beta / metabolism
  • Macrophages, Alveolar / enzymology*
  • Macrophages, Alveolar / microbiology
  • Male
  • Mice
  • Middle Aged
  • Pneumonia, Bacterial / enzymology*
  • Pneumonia, Bacterial / microbiology
  • Pulmonary Disease, Chronic Obstructive / enzymology*
  • Pulmonary Disease, Chronic Obstructive / microbiology


  • CCL20 protein, mouse
  • CCL3 protein, human
  • Ccl3 protein, mouse
  • Chemokine CCL20
  • Chemokine CCL3
  • IL1B protein, human
  • Interleukin-1beta
  • DPP4 protein, human
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse