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

• Published in: The Journal of immunology (1950) Vol. 199; no. 6; pp. 2128 - 2139
• Main Authors: Ahmed, Afsar U, Yim, Howard C H, Alorro, Mariah, Ernst, Matthias, Williams, Bryan R G
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 15.09.2017
• Subjects: 1-Phosphatidylinositol 3-kinase; Activation; Colitis; Colon; Dextran; Epithelium; ILK protein; Inflammatory bowel disease; Inflammatory bowel diseases; Intestine; Leukocytes (neutrophilic); Mice; Mucosa; Myeloid cells; NF-κB protein; Pathology; Rodents; Signal transduction; Sodium; Sodium sulfate; Stat3 protein; Sulfates
• DOI: 10.4049/jimmunol.1700125
• ISSN: 0022-1767

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-κB 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.