Dependence of intestinal granuloma formation on unique myeloid DC-like cells
Atsushi Mizoguchi, Atsushiro Ogawa, Hidetoshi Takedatsu, Ken Sugimoto, Yasuyo Shimomura, Katsunori Shirane, Kiyotaka Nagahama, Takashi Nagaishi, Emiko Mizoguchi, Richard S. Blumberg, Atul K. Bhan
Atsushi Mizoguchi, Atsushiro Ogawa, Hidetoshi Takedatsu, Ken Sugimoto, Yasuyo Shimomura, Katsunori Shirane, Kiyotaka Nagahama, Takashi Nagaishi, Emiko Mizoguchi, Richard S. Blumberg, Atul K. Bhan
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Research Article Immunology

Dependence of intestinal granuloma formation on unique myeloid DC-like cells

Abstract

Granulomas represent a localized inflammatory reaction that is characteristically observed in many inflammatory conditions. However, the mechanisms of granuloma formation have not been fully defined. Herein we demonstrate, by using experimental models of intestinal inflammation, that a unique CD11c+ DC-like cell subset that exhibits phenotypic and functional features of immature myeloid DCs and is characterized by the expression of a macrophage marker (F4/80) produces large amounts of IL-23 and directly induces the development of granulomas under a Th1-predominant intestinal inflammatory condition. Importantly, both IL-4 and IgG contribute to the suppression of F4/80+ DC-like cell–mediated granuloma formation by regulating the function and differentiation of this cell subset. In addition, enteric flora is required for the F4/80+ DC-like cell–mediated granuloma formation. Collectively, our data provide what we believe are novel insights into the involvement of F4/80+ DC-like cells in intestinal granuloma formation and demonstrate the role of host (IL-4 and IgG) and environmental (enteric flora) factors that regulate this function.

Authors

Atsushi Mizoguchi, Atsushiro Ogawa, Hidetoshi Takedatsu, Ken Sugimoto, Yasuyo Shimomura, Katsunori Shirane, Kiyotaka Nagahama, Takashi Nagaishi, Emiko Mizoguchi, Richard S. Blumberg, Atul K. Bhan

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Figure 4

IL-12p40 but not IFN-γ is involved in the development of intestinal granulomas.

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IL-12p40 but not IFN-γ is involved in the development of intestinal gran...
(A) RPA using RNA from ileocecal junction areas shows that IL-12p40 but not p35 is detectable in αμIL4TKO but not TCRαKO (TCRα) mice (24 weeks of age). (B) Colonic LP cells (2 × 105) from WT (n = 5), TCRαKO (n = 7), αμDKO (n = 7), αIL4DKO (αIL4) (n = 7), and αμIL4TKO (n = 9) mice were cultured for 48 hours, and the culture supernatants were subjected to ELISA. There was a significant increase (**P < 0.001) of IL-12p40 and IFN-γ production by colonic LP cells from αμIL4TKO mice compared with αμDKO, αIL4DKO, TCRαKO, and WT mice. (C) Typical granulomatous inflammation characterized by nodular collections of epithelioid cells surrounded by lymphoid cells is still detectable in αμIL4IFNQKO mice. The frequency and severity of granulomas were similar in αμIL4TKO and αμIL4IFNQKO mice (data not shown). (D and E) Anti–IL-12p40 mAbs (0.5 mg) were administered weekly to αμIL4TKO mice (16 weeks of age) that had developed colitis, as indicated by the presence of diarrhea, and the mice were sacrificed at 24 weeks of age. Granulomatous inflammation, identified grossly as nodular lesions, is present in the ileocecal junction area of the αμIL4TKO mice administered control Igs (arrow) but not those administered anti–IL-12p40 mAbs (arrowhead). Granulomatous inflammation was graded as follows: 0, no granulomas present; 1, aggregation of cells without definite granuloma formation that is characterized by nodular collections of epithelioid cells surrounded by lymphocytes; 2, an occasional small granuloma present; 3, a few large granulomas present; and 4, many granulomas present. Results are summarized in E. Gran, granulomas.