Induction of complement C3a receptor responses by kallikrein-related peptidase 14

J Immunol. 2013 Oct 1;191(7):3858-66. doi: 10.4049/jimmunol.1202999. Epub 2013 Sep 6.


Activation of the complement system is primarily initiated by pathogen- and damage-associated molecular patterns on cellular surfaces. However, there is increasing evidence for direct activation of individual complement components by extrinsic proteinases as part of an intricate crosstalk between physiological effector systems. We hypothesized that kallikrein-related peptidases (KLKs), previously known to regulate inflammation via proteinase-activated receptors, can also play a substantial role in innate immune responses via complement. Indeed, KLKs exemplified by KLK14 were efficiently able to cleave C3, the point of convergence of the complement cascade, indicating a potential modulation of C3-mediated functions. By using in vitro fragmentation assays, mass spectrometric analysis, and cell signaling measurements, we pinpointed the generation of the C3a fragment of C3 as a product with potential biological activity released by the proteolytic action of KLK14. Using mice with various complement deficiencies, we demonstrated that the intraplantar administration of KLK14 results in C3-associated paw edema. The edema response was dependent on the presence of the receptor for C3a but was not associated with the receptor for the downstream complement effector C5a. Our findings point to C3 as one of the potential substrates of KLKs during inflammation. Given the wide distribution of the KLKs in tissues and biological fluids where complement components may also be expressed, we suggest that via C3 processing, tissue-localized KLKs can play an extrinsic complement-related role during activation of the innate immune response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Complement Activation / immunology
  • Complement C3 / genetics
  • Complement C3 / immunology
  • Complement C3 / metabolism
  • Complement C3a / immunology
  • Complement C3a / metabolism
  • Complement C5 / genetics
  • Complement C5 / immunology
  • Complement C5 / metabolism
  • Disease Models, Animal
  • Edema / genetics
  • Edema / immunology
  • Edema / metabolism
  • Humans
  • Kallikreins / administration & dosage
  • Kallikreins / immunology
  • Kallikreins / metabolism*
  • Mice
  • Mice, Knockout
  • Proteolysis
  • Receptors, Complement / genetics
  • Receptors, Complement / metabolism*


  • Complement C3
  • Complement C5
  • Receptors, Complement
  • complement C3a receptor
  • Complement C3a
  • KLK14 protein, human
  • Kallikreins