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miR-15a/16 regulates macrophage phagocytosis after bacterial infection
#MMPMID25261473
Moon HG
; Yang J
; Zheng Y
; Jin Y
J Immunol
2014[Nov]; 193
(9
): 4558-67
PMID25261473
show ga
Bacterial infection and its associated sepsis are devastating clinical entities
that lead to high mortality and morbidity in critically ill patients.
Phagocytosis, along with other innate immune responses, exerts crucial impacts on
the outcomes of these patients. MicroRNAs (miRNAs) are a novel class of
regulatory noncoding RNAs that target specific mRNAs for modulation of
translation and expression of a targeted protein. The roles of miRNAs in host
defense against bacterial sepsis remain unclear. We found that bacterial
infections and/or bacterial-derived LPS enhanced the level of miR-15a/16 in bone
marrow-derived macrophages (BMDMs). Deletion of miR-15a/16 (miR-15a/16(-/-)) in
myeloid cells significantly decreased the bacterial infection-associated
mortality in sepsis mouse models. Moreover, miR-15a/16 deficiency
(miR-15a/16(-/-)) resulted in augmented phagocytosis and generation of
mitochondrial reactive oxygen species in BMDMs. Supportively, overexpression of
miR-15a/16 using miRNA mimics led to decreased phagocytosis and decreased
generation of mitochondrial reactive oxygen species. Mechanistically, deletion of
miR-15a/16 upregulated the expression of TLR4 via targeting the principle
transcriptional regulator PU.1 locating on the promoter region of TLR4, and
further modulated the downstream signaling molecules of TLR4, including Rho
GTPase Cdc 42 and TRAF6. In addition, deficiency of miR-15a/16 also facilitated
TLR4-mediated proinflammatory cytokine/chemokine release from BMDMs at the
initial phase of infections. Taken together, miR-15a/16 altered phagocytosis and
bacterial clearance by targeting, at least partially, on the TLR4-associated
pathways, subsequently affecting the survival of septic mice.
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