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J Immunol. 2017 Aug 9. pii: ji1700125. doi: 10.4049/jimmunol.1700125. [Epub ahead of print]

Integrin-Linked Kinase Expression in Myeloid Cells Promotes Inflammatory Signaling during Experimental Colitis.

Author information

1
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.
2
Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
3
Cancer and Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia; and.
4
School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
5
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; bryan.williams@hudson.org.au.

Abstract

The pathology of inflammatory bowel diseases is driven by the inflammatory signaling pathways associated with mucosal epithelial damage. Myeloid cells are known to play an essential role in mediating epithelial inflammatory responses during injury. However, the precise role of these cells in stimulating intestinal inflammation and the subsequent tissue damage is unclear. In this article, we show that expression of integrin-linked kinase (ILK) in myeloid cells is critical for the epithelial inflammatory signaling during colitis induced by dextran sodium sulfate. Myeloid ILK (M-ILK) deficiency significantly ameliorates the pathology of experimental colitis. In response to dextran sodium sulfate, colonic infiltration of neutrophils and inflammatory cytokine production are impaired in M-ILK-deficient mice, and activation of epithelial NF-╬║B and PI3K signaling pathways are restricted by the M-ILK deficiency. In contrast, reduced epithelial damage in M-ILK-deficient mice is correlated with elevated levels of epithelial Stat3 activation and proliferation. Moreover, M-ILK-dependent inflammatory signaling in the mucosal epithelium can be therapeutically targeted by the pharmacological inhibition of ILK during experimental colitis. Collectively, these findings identify M-ILK as a critical regulator of epithelial inflammatory signaling pathways during colitis and, as a consequence, targeting M-ILK could provide therapeutic benefit.

PMID:
28794235
DOI:
10.4049/jimmunol.1700125

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