Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 ( Cdcs1 ) locus

Abstract

Genetic modifier loci influence the phenotypic expression of many Mendelian traits; insight into disease pathogenesis gained from their identification in animal disease models may impact the treatment of human multigenic disorders. We previously described an innate immune-driven model of spontaneous ulcerative colitis in T-bet −/− .Rag2 −/− double-deficient mice that resembles human ulcerative colitis. On a BALB/c background, this disease is highly penetrant and results in the development of colorectal cancer. However, we observed that colitis in T-bet −/− .Rag2 −/− mice on a C57BL/6 background was significantly less severe. Quantitative trait locus analysis using an N2 backcross strategy revealed a single major quantitative trait locus on chromosome 3 that mapped to the Cdcs1 (cytokine deficiency-induced colitis susceptibility-1) locus previously identified in the Il10 −/− and Gnai2 −/− colitis models. Congenic introduction of the susceptible Cdcs1 interval from C3H/He into the C57BL/6 background restored colitis severity. Bone marrow reconstitution experiments further mapped the effect of host genetics on disease severity to the hematopoietic compartment. There were distinct differences in the expression of several Cdcs1 genes in bone marrow-derived dendritic cells from Cdcs1 congenic mice. We conclude that the Cdcs1 locus controls colitis severity in T-bet −/− .Rag2 −/− mice through innate immune cells.

Nod/Ripk2 signaling in dendritic cells activates IL-17A–secreting innate lymphoid cells and drives colitis inT-bet−/−.Rag2−/−(TRUC) mice

“…Nod2 −/− vs. 2.3 in TRUC.Nod1 +/+ .Nod2 −/− littermate controls, P = 0.0070). This result is consistent with the dominant role of Gram-negative bacteria, which can activate both Nod1 and Nod2, in TRUC pathogenesis (1,2,24). It argues further, that, in TRUC colitis, there is no alternative upstream signal driving Ripk2 activation independently of Nod1 or Nod2 (38).…”

“…in a blinded fashion. The parameters mononuclear cell infiltration, polymorphonuclear cell infiltration, epithelial hyperplasia, and epithelial injury were scored as absent (0), mild (1), moderate (2), or severe (3), giving a total score of 0-12 (24).…”

The Microbiome in Infectious Disease and Inflammation

“…Intestinal inflammation caused by either a chemical inducer, such as dextran sulfate sodium (DSS), or a genetic deficiency, such as Il10 deficiency, can also alter the composition of the intestinal microbiota, resulting in a reduction in both the total number of resident intestinal bacteria and bacterial diversity ( 47 ). Studies have shown a change in composition of the microbiota in T-bet −/− Rag2 −/− ulcerative colitis (TRUC) mice, which have a T-bet deficiency in the innate immune system and develop spontaneous colitis with high penetrance on a BALB/c background ( 36 , 49 ). TRUC colitis is attributed to the hyperproduction of tumor necrosis factor (TNF)-α by dendritic cells ( DCs ), because T-bet is a negative regulator of TNF-α transcription ( 36 ).…”

Molecular Control of Steady-State Dendritic Cell Maturation and Immune Homeostasis

“…Nevertheless, commensal sampling and signals in DCs that lead to colitis can be either MyD88-dependent or -independent, so T-bet may preferentially regulate transcriptional programs initiated by signals from the latter (69, 201–203). T-bet −/− /RAG2 −/− DC-driven colitis is most severe in the BALB/c genetic background compared with that of C57BL/6, as a result of the congenic differences in the Cdcs1 locus (cytokine deficiency–induced colitis susceptibility-1), a largely uncharacterized disease-susceptibility region that also plays a role in colitis associated with IL-10 deficiency (204, 205). Further analysis of Cdcs1 gene products, the signaling pathways that induce transcription of the Cdcs1 locus in intestinal DCs, and whether T-bet regulates this locus should provide insight into the colitogenic responses of T-bet-deficient DCs.…”