CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice

Oscar Medina-Contreras et al . J Clin Invest. 121 . 4787-4795 (2011)

Speaker: Chia-Lun Tsai (蔡佳倫)                                  Time: 13:10-14:00, March 28, 2012

Commentator: Dr. Chih-Peng Chang (張志鵬老師)    Place: Room 601

Abstract

In the intestine, immune reactivity toward commensal flora must be restrained to prevent pathological inflammation, such as in Crohn’s disease and ulcerative colitis. There are numerous mechanical, physical, and immunological mechanisms that play crucial roles in maintaining intestinalhomeostasis . A number of functionally distinct APC populations exist in the mucosal lamina propria (LP) below the intestinal epithelium, but their relative contributions to inflammation remain unclear. The chemokine receptor CX3CR1 is expressed by LP DCs and macrophages . In this study authors used Cx3cr1^gfp/gfp reporter mice to observe that GFP (CX3CR1) was expressed by CD11c^– and CD11c⁺ macrophages, but not by CD11b– or CD11b+ DCs, in both the small and large intestine using  by flow cytometry and qRT-PCR. GFP (CX3CR1) was reduced in  LP macrophages in CX3CR1^- and CX3CL1-deficient mice. And the authors analyzed the mLNs (mesentery LNs) from Cx3cr1^gfp/gfp, Cx3cr1^–/– and Cx3cl1^–/– mice for signs of bacterial translocation by total mLN cell suspensions cultured under aerobic conditions in  LB blood agar plates. The results revealed the presence of large numbers of bacteria in these mice. And they used mice model of acute colitis induced by DSS, in Cx3cr1^gfp/gfp and Cx3cr1^–/– mice. These mice exhibited significantly enhanced signs of intestinal disease when compared with Cx3cr1^+/+ mice, as defined by increases in disease activity index (DAI), and the histological analysis also showed greater tissue damage and inflammatory infiltrate in DSS-treated Cx3cr1^gfp/gfp and Cx3cr1^–/– mice when compared with Cx3cr1^+/+ mice.IL-17 responses contribute to enhanced colitis in Cx3cr1^gfp/gfp mice by flow cytometry assay. IL-17 also contributes the severity of colitis in DSS-treated Cx3cr1^gfp/gfp mice after adoptive transfer of Cx3cr1^gfp/gfp or Cx3cr1^+/+ BMDMs. In summary, the authors show in this study that the roles for the CX3CR1/CX3CL1 axis in the intestinal mucosa  will likely direct efforts toward therapeutic intervention for mucosal inflammatory disorders such as IBD.

References

1.     Regulatory lymphocytes and intestinal inflammation. Izcue A et al . Annu Rev Immunol. 27 , 313–338 (2009)