Background/Purpose:

We previously demonstrated that FLIP in myeloid linage cells is necessary for neutrophil homeostasis and macrophage differentiation.  Therefore studies were performed to determine the in vivo role of FLIP in CD11c positive dendritic cells. 

Methods:

Mice with Flip deficient in dendritic cells (Flip ^f/f, CD11c ^cre/+) were generated by crossing Flip ^f/f mice with a CD11c^cre transgenic line.  Cell types and differential in peripheral blood were determined by complete blood count.  Cell types from different organs were determined by immunophenotyping employing multi-color fluorochrome-conjugated cell marker antibodies, analyzed by Flow cytometry.  Age and gender matched mice were used as controls.

Results:

Many phenotypic disorders developed in Flip ^f/f, CD11c ^cre/+ mice, including growth retardation (significantly reduced body size and weight) with increased severity in females, and approximately 15% died prematurely.  Almost 40% of the mice that reached 4 months of age or older spontaneously experienced an arthropathy characterized by joint swelling and/or deformity.  Proteinuria was not observed.  All Flip ^f/f, CD11c ^cre/+ mice developed lymphadenopathy, but the spleens were normal both in size and in cell numbers.  Immunophenotype analysis demonstrated a significant reduction CD11c,CD8 dendritic cells in the spleens of the Flip ^f/f, CD11c ^cre/+ mice.  In Flip ^f/f, CD11c ^cre/+ mice granulocytes were significantly increased in peripheral blood, spleens, lymph nodes and peritoneal cavities and they infiltrated in all organs examined.  Although circulating monocytes were significantly increased in Flip ^f/f, CD11c ^cre/+ mice, there is no difference in macrophage numbers in the organs examined.  Although B cell numbers were increased in the lymph nodes of Flip ^f/f, CD11c ^cre/+ mice, which may contribute to lymphadenopathy, neither B cells nor T cells were increased in the peripheral blood or other organs.  

Conclusion:

The survival of CD11c+ dendritic cells in the spleen requires FLIP.  The deletion of FLIP in CD11c dendritic cells also results in increased circulating neutrophils and a multiorgan neutrophil infiltration.  A substantial proportion of these mice develop an arthropathy but proteinuria was not observed.  FLIP expression in CD11c+ dendritic cells is necessary for survival in the spleen and for neutrophil homeostasis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/flip-in-dendritic-cells-may-regulate-hematopoietic-homeostasis-and-modulating-inflammation-and-immunity/