Sialylation regulates neutrophil transepithelial migration, CD11b/CD18 activation, and intestinal mucosal inflammatory function

Abstract

Neutrophils (PMNs) play a critical role in clearing invading microbes and promoting tissue repair following infection/injury. However, dysregulated PMN trafficking and associated tissue damage is pathognomonic of numerous inflammatory mucosal diseases. The final step in PMN influx into mucosal lined organs (including the lungs, kidneys, skin and gut) involves transepithelial migration (TEpM). The b2-integrin CD11b/CD18 plays an important role in mediating PMN intestinal trafficking with recent studies highlighting that terminal Fucose and GlcNAc glycans on CD11b/CD18 can be targeted to reduce TEpM. However, the role of the most abundant terminal glycan, Sialic acid (Sia), in regulating PMN epithelial influx and mucosal inflammatory function is not well understood. Here we demonstrate that inhibiting sialidase mediated removal of a2-3 linked Sia from CD11b/CD18 inhibits PMN migration across intestinal epithelium in vitro and in vivo. Sialylation was also found to regulate critical PMN inflammatory effector functions including degranulation and superoxide release. Finally, we demonstrate that sialidase inhibition reduces bacterial peptide mediated CD11b/CD18 activation in PMN and blocks downstream intracellular signaling mediated by Spleen tyrosine kinase (Syk) and p38 MAP kinase. These findings suggest that sialylated glycans on CD11b/CD18 represent novel targets for ameliorating PMN mediated tissue destruction in inflammatory mucosal diseases.

Targeting adrenergic receptors to mitigate invariant natural killer T cells-induced acute liver injury

“…In this context, we observed that in vitro adrenergic stimulation impaired the acquisition of a more inflammatory/invasive profile by neutrophils (Ly6G + CD11b high ) treated with NE or Phe before incubation with αGC-pulsed AML12 cells. 49 , 50 In line with this, WT animals exhibited higher hepatic leukocyte counts after αGC administration than the Adra2 ac −/− mice. Furthermore, in the latter, the infiltrating neutrophils and myeloid-derived CD11b + F4/80 + mice expressed lower levels of CD11b on their surface, indicating a lesser inflammatory/invasive profile due to adrenergic signaling.…”

SIGLEC-5/14 Inhibits CD11b/CD18 Integrin Activation and Neutrophil-Mediated Tumor Cell Cytotoxicity

“…Based on these findings and our own data, we could speculate that the regulation of CD11b/CD18 activation by SIGLEC-5/14 operates in a similar fashion [42]. Nevertheless, we cannot rule out the possibility of SIGLEC-5/14-mediated restriction of integrin activation in cis [43].…”