1. ArhGAP15, a RacGAP, Acts as a Temporal Signaling Regulator of Mac-1 Affinity in Sterile Inflammation.
- Author
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Margraf, Andreas, Cappenberg, Anika, Vadillo, Eduardo, Ludwig, Nadine, Thomas, Katharina, Körner, Katharina, Zondler, Lisa, Rossaint, Jan, Germena, Giulia, Hirsch, Emilio, and Zarbock, Alexander
- Subjects
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LEUCOCYTES , *INFLAMMATION , *KIDNEY injuries , *NEUTROPHILS - Abstract
During inflammation, leukocyte recruitment has to be tightly controlled to prevent overwhelming leukocyte infiltration, activation, and, consequently, organ damage. A central regulator of leukocyte recruitment is Rac1. In this study, we analyzed the effects of the RacGAP ArhGAP15 on leukocyte recruitment. Using ArhGAP15-deficient mice, reduced neutrophil adhesion and transmigration in the TNF-a-inflamed cremaster muscle and a prolongation of chemokine-dependent leukocyte adhesion could be observed. In a murine model of sterile kidney injury, reduced neutrophil infiltration, and serum creatinine levels were apparent. Further in vitro and in vivo analyses revealed a defective intravascular crawling capacity, resulting from increased affinity of the b2-integrin Mac-1 after prolonged chemokine stimulation of neutrophils. LFA-1 activity regulation was not affected. Summarizing, ArhGAP15 specifically regulates Mac-1, but not LFA-1, and affects leukocyte recruitment by controlling postadhesion strengthening and intravascular crawling in a Mac-1-dependent manner. In conclusion, ArhGAP15 is involved in the time-dependent regulation of leukocyte postadhesion in sterile inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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