STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: A critical role of STAT3 in innate immunity

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional mediator for many cytokines and is essential for normal embryonic development. We have generated a unique strain of mice with tissue-specific disruption of STAT3 in bone marrow cells during hematopoiesis. This specific STAT3 deletion causes death of these mice within 4 -6 weeks after birth with Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation.

Role of Stat3 in suppressing anti-tumor immunity

“…Mice with induced deletion including the tyrosine 705 in Stat3 allele(s) in the hematopoietic system or macrophages exhibit enhanced Th1 activity and can suffer from chronic enterocolitis [11,45,46]. Consistent with the findings in mouse studies, an indication that Stat3 can inhibit pro-inflammatory signals in human is provided by recent studies identifying mutations in Stat3 in patients with hyper-IgE syndrome (HIES) [47,48].…”

“…The ability of Stat3 to inhibit expression of similar immunostimulatory molecules in immune cells in tumor setting and in normal cells has also been demonstrated [4]. The underlying molecular mechanism(s) for downregulating Th1 immune responses remain fully unexplored, although it has been suggested that Stat3 has an antagonistic effect on immunostimulatory effects of NF-κB [11,12] and Stat1 [13], both of which are critical for inducing Th1 immune responses.…”

STAT3 in immune responses and inflammatory bowel diseases

“…Our evidence has shown that one strain of mice with bone marrow cell specific STAT3 KO have developed IBD/Crohn's disease (CD)-like pathogenesis [64]. Importantly, STAT3 deletion in dendritic cells in our mice may also have contributed in the development of these syndromes of inflammation.…”

“…However, little was known about how these subsets of DCs are generated until recently. It is interesting to point out that we have recently shown that in the mice with STAT3 knock out in bone marrow cells, IL-12 and IFN-γ were all elevated [64], which resembles possible selective activation of CD8+ DCs. or /and absence of pDCs [83].…”

Role of STAT3 in inflammatory bowel disease

“…Since classical knockout of the STAT3 gene in mice resulted in early embryonic lethality [18] , various cell type-specific STAT3 knockout mice were generated to elucidate the functional relevance of STAT3 [15,[19][20][21][22][23] . Acquired immune cells, especially CD4 + T cells, have a considerable ability to induce the development and exacerbation of not only CD-like, but also UClike experimental colitis [24][25][26][27] .…”