CHANG-DISSERTATION-2021.pdf (5.22 MB)
The Role of G alpha 13 in Integrin-dependent Neutrophil Migration
thesisposted on 2021-12-01, 00:00 authored by Claire Wei-Ju Chang
Inflammation play important roles in many diseases, including sepsis, type II diabetes, and atherosclerosis. Alleviating inflammatory responses could be an effective strategy to treat inflammation-associated diseases. Neutrophils are the first responder to inflammatory sites. Their primary function is to clear out foreign invaders and ameliorate tissue damage. However, excess neutrophil recruitment can cause adverse effects such as tissue injury. Therefore, regulating neutrophil function is a critical issue for immunity and autoimmunity. Integrins transmit signals bidirectional and play an important role in neutrophil migration. Neutrophil migration requires beta 2 integrins and chemoattractant receptor signaling for motility and directionality. G protein subunit G alpha13 was proposed to facilitate cell migration by activating the RhoA signaling pathway. However, G alpha 13 also interacts with integrins and mediates integrin outside-in signaling. The possible role of G alpha13-integrin interaction in migration is unclear. In this study, we show the importance of G alpha 13-mediated integrin outside-in signaling in neutrophil migration, as G alpha13 knockout or inhibition of G alpha 13-beta 2 interaction using a beta 2-derived ExE motif peptide (MB2mP6) inhibited transendothelial neutrophil migration. Although ICAM-1 and fibrinogen are both integrin beta 2 ligands, the G alpha 13-dependent neutrophil migration is ICAM-1 dependent but not fibrinogen dependent. In addition, the MB2mP6 selectively abolished outside-in signaling without affecting integrin ligation. Furthermore, we demonstrate that G alpha 13 knockout or MB2mP6 reduces the neutrophil migration velocity without affecting migration directionality. Thus, we have uncovered a new mechanism that serves as the acceleration pedal for neutrophil migration without turning the steering wheel.
Degree GrantorUniversity of Illinois at Chicago
Degree namePhD, Doctor of Philosophy
Committee MemberEddington, David T Khetani, Salman R Minshall, Richard D de Lanerolle, Primal
Submitted dateDecember 2021