| First Author | Sun X | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 1 | Pages | 357-65 |
| PubMed ID | 23180818 | Mgi Jnum | J:190841 |
| Mgi Id | MGI:5449783 | Doi | 10.4049/jimmunol.1201825 |
| Citation | Sun X, et al. (2013) Phosphatidylinositol 3-Kinase-gamma Signaling Promotes Campylobacter jejuni-Induced Colitis through Neutrophil Recruitment in Mice. J Immunol 190(1):357-65 |
| abstractText | Crypt abscesses caused by excessive neutrophil accumulation are prominent features of human campylobacteriosis and its associated pathology. The molecular and cellular events responsible for this pathological situation are currently unknown. We investigated the contribution of PI3K-gamma signaling in Campylobacter jejuni-induced neutrophil accumulation and intestinal inflammation. Germ-free and specific pathogen-free Il10(-/-) and germ-free Il10(-/-);Rag2(-/-) mice were infected with C. jejuni (10(9) CFU/mouse). PI3K-gamma signaling was manipulated using either the pharmacological PI3K-gamma inhibitor AS252424 (i.p. 10 mg/kg daily) or genetically using Pi3k-gamma(-/-) mice. After up to 14 d, inflammation was assessed histologically and by measuring levels of colonic Il1beta, Cxcl2, and Il17a mRNA. Neutrophils were depleted using anti-Gr1 Ab (i.p. 0.5 mg/mouse/every 3 d). Using germ-free Il10(-/-);Rag2(-/-) mice, we observed that innate immune cells are the main cellular compartment responsible for campylobacteriosis. Pharmacological blockade of PI3K-gamma signaling diminished C. jejuni-induced intestinal inflammation, neutrophil accumulation, and NF-kappaB activity, which correlated with reduced Il1beta (77%), Cxcl2 (73%), and Il17a (72%) mRNA accumulation. Moreover, Pi3k-gamma(-/-) mice pretreated with anti-IL-10R were resistant to C. jejuni-induced intestinal inflammation compared with Wt mice. This improvement was accompanied by a reduction of C. jejuni translocation into the colon and extraintestinal tissues and by attenuation of neutrophil migratory capacity. Furthermore, neutrophil depletion attenuated C. jejuni-induced crypt abscesses and intestinal inflammation. Our findings indicate that C. jejuni-induced PI3K-gamma signaling mediates neutrophil recruitment and intestinal inflammation in Il10(-/-) mice. Selective pharmacological inhibition of PI3K-gamma may represent a novel means to alleviate severe cases of campylobacteriosis, especially in antibiotic-resistant strains. |
