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2014 ; 516
(7530
): 246-9
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Dietary modulation of the microbiome affects autoinflammatory disease
#MMPMID25274309
Lukens JR
; Gurung P
; Vogel P
; Johnson GR
; Carter RA
; McGoldrick DJ
; Bandi SR
; Calabrese CR
; Vande Walle L
; Lamkanfi M
; Kanneganti TD
Nature
2014[Dec]; 516
(7530
): 246-9
PMID25274309
show ga
The incidences of chronic inflammatory disorders have increased considerably over
the past three decades. Recent shifts in dietary consumption may have contributed
importantly to this surge, but how dietary consumption modulates inflammatory
disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro
missense mutation in the Pombe Cdc15 homology family protein PSTPIP2
(proline-serine-threonine phosphatase interacting protein 2), spontaneously
develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis
in humans. Recent reports demonstrated a crucial role for interleukin-1? (IL-1?)
in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3
failed to rescue Pstpip2(cmo) mice from inflammatory bone disease. Thus, the
upstream mechanisms controlling IL-1? production in Pstpip2(cmo) mice remain to
be identified. In addition, the environmental factors driving IL-1?-dependent
inflammatory bone erosion are unknown. Here we show that the intestinal
microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of
Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and
cholesterol maintained a normal body weight, but were markedly protected against
inflammatory bone disease and bone erosion. Diet-induced protection against
osteomyelitis was accompanied by marked reductions in intestinal Prevotella
levels and significantly reduced pro-IL-1? expression in distant neutrophils.
Furthermore, pro-IL-1? expression was also decreased in Pstpip2(cmo) mice treated
with antibiotics, and in wild-type mice that were kept under germ-free
conditions. We further demonstrate that combined deletion of caspases 1 and 8 was
required for protection against IL-1?-dependent inflammatory bone disease,
whereas the deletion of either caspase alone or of elastase or neutrophil
proteinase 3 failed to prevent inflammatory disease. Collectively, this work
reveals diet-associated changes in the intestinal microbiome as a crucial factor
regulating inflammasome- and caspase-8-mediated maturation of IL-1? and
osteomyelitis in Pstpip2(cmo) mice.
|*Diet, High-Fat
[MESH]
|Adaptor Proteins, Signal Transducing/deficiency/genetics
[MESH]
free
free
free
