IL-6 deficiency promotes colitis by recruiting Ly6Chi monocytes into inflamed colon tissues in a CCL2-CCR2-dependent manner

Abstract

Interleukin 6 (IL-6) is a pleiotropic cytokine that is elevated in inflammatory bowel disease. However, the role of IL-6 deficiency in colitis is not well-defined. Some IL-6 and IL-6 receptor antagonists are associated with severe gastrointestinal immune adverse effects, but the mechanisms of the effects are not clear. This study aimed to investigate the effect of IL-6 in ulcerative colitis in Il6^-/- mice. Results indicated that physiological deficiency of IL-6 promoted the development of colitis. Moreover, IL-6 deficiency significantly increased the mRNA levels of monocytes chemokine Ccl2 and its receptor Ccr2 in colon tissues. Similarly, the percentage of Ly6C^high monocytes and neutrophils were increased in the colon of Il6^-/- mice. Intestinal crypts more strongly increased the migration of Il6^-/- macrophages than wild-type ones. Moreover, Il6^-/- macrophages promoted the migration of neutrophils. Most importantly, RS102895, an antagonist of CCR2, diminished chemotaxis of macrophages and inhibited colitis in Il6^-/- mice. Collectively, these results indicate that Il6^-/- macrophages migrate to inflamed colon tissues and recruit neutrophils, thereby promoting the effect of Il6^-/- on colitis. This study expands our understanding on the effect of IL-6 deficiency in colitis and the development of gastrointestinal immune adverse effects.

Keywords: CCL2; Colitis; IL-6; Monocytes.