In an environment replete with microbial invaders, mammals must mount a successful defense against microbes in cutaneous wounds, trauma, and tissue injury. Staphylococcus aureus and Pseudomonas aeruginosa are the most common bacteria isolated from chronic skin wounds and among the most prominent pathogens in community-acquired and nosocomial infections, and these organisms readily develop antibiotic resistance. The matricellular protein CCN1 has recently emerged as an important multifunctional regulator of the wound healing process. CCN1 directly induces myofibroblast senescence through integrin ?6?1 in the maturation phase of wound repair, thereby initiating matrix remodeling and dampening fibrosis. Recent studies have uncovered additional unexpected but critical activities of CCN1 in wound repair: (1) CCN1 acts as a bridging molecule and triggers the phagocytic removal of apoptotic neutrophils in wounds, resulting in resolution of inflammation and allowing healing to proceed. (2) CCN1 promotes clearance of S. aureus and P. aeruginosa by inducing their phagocytosis by macrophages and neutrophils. Bacterial clearance is impaired in knockin mice expressing a CCN1 mutant unable to bind integrin ?v?3/?v?5, and accelerated in mice injected with purified CCN1 protein. Moreover, treatment of excisional wounds with purified CCN1 protein accelerates closure in diabetic mice. Based on these findings, we hypothesize that CCN1 is a multifunctional protein that regulates disparate aspects of wound healing, including clearance of infecting microbes, resolution of inflammation, and indirectly lead to enhanced granulation tissue formation. We will scrutinize this hypothesis in three specific aims:
Aim 1 evaluates the role of CCN1 in bacterial clearance in animal models of infection;
Aim 2 dissects the molecular mechanism of CCN1 action in bacterial clearance;
and Aim 3 investigates how CCN1 accelerates diabetic wound healing. Together, these studies will illuminate the mechanism of a novel arsenal in innate immunity against microbial invaders and may prompt new approaches toward the management of antibiotic-resistant infections and chronic non-healing wounds.
Wound healing is a complex, multi-step process that includes combating microbial invaders. A growing number of antibiotic resistant bacteria have emerged in the last several decades and are becoming major problems in hospital- and community-acquired infections, some of which are associated with high mortality. Microbial infection and persistent inflammation also contribute to chronic non-healing wounds, which may require amputation. This proposal seeks to investigate novel mechanisms of microbial clearance and inflammation resolution. We anticipate that our results will prompt new therapeutic strategies that may reduce the morbidity and mortality associated with impaired wound healing.
| Jun, Joon-Il; Lau, Lester F (2018) Resolution of organ fibrosis. J Clin Invest 128:97-107 |
| Kim, Ki-Hyun; Won, Jong Hoon; Cheng, Naiyuan et al. (2018) The matricellular protein CCN1 in tissue injury repair. J Cell Commun Signal 12:273-279 |
| Vaidya, Ruben; Zambrano, Ronald; Hummler, Julia K et al. (2017) Recombinant CCN1 prevents hyperoxia-induced lung injury in neonatal rats. Pediatr Res 82:863-871 |
| Jun, Joon-Ii; Lau, Lester F (2017) CCN2 induces cellular senescence in fibroblasts. J Cell Commun Signal 11:15-23 |
| Monzon, Ricardo I; Kim, Ki-Hyun; Lau, Lester F (2017) Construction and Analysis of an Allelic Series of Ccn1 Knockin Mice. Methods Mol Biol 1489:361-376 |
| Lau, Lester F (2016) Cell surface receptors for CCN proteins. J Cell Commun Signal 10:121-7 |
| Chen, C-C; Kim, K-H; Lau, L F (2016) The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation. Oncogene 35:1314-23 |
| Jun, Joon-Il; Kim, Ki-Hyun; Lau, Lester F (2015) The matricellular protein CCN1 mediates neutrophil efferocytosis in cutaneous wound healing. Nat Commun 6:7386 |
| Choi, J S; Kim, K-H; Lau, L F (2015) The matricellular protein CCN1 promotes mucosal healing in murine colitis through IL-6. Mucosal Immunol 8:1285-96 |
| Zemans, Rachel L; McClendon, Jazalle; Aschner, Yael et al. (2013) Role of ?-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 304:L415-27 |
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