Cell-Intrinsic Wnt4 Influences Conventional Dendritic Cell Fate Determination to Suppress Type 2 Immunity

Abstract

Whether conventional dendritic cells (cDC) acquire subset identity under direction of Wnt family glycoproteins is unknown. We demonstrate that Wnt4, a b-catenin-independent Wnt ligand, is produced by both hematopoietic and nonhematopoietic cells and is both necessary and sufficient for preconventional DC1/cDC1 maintenance. Whereas bone marrow cDC precursors undergo phosphoJNK/c-Jun activation upon Wnt4 treatment, loss of cDC Wnt4 in CD11c Cre Wnt4 flox/flox mice impaired differentiation of CD24 + , Clec9A + , CD103 + cDC1 compared with CD11c Cre controls. Conversely, single-cell RNA sequencing analysis of bone marrow revealed a 2-fold increase in cDC2 gene signature genes, and flow cytometry demonstrated increased numbers of SIRP-a + cDC2 amid lack of Wnt4. Increased cDC2 numbers due to CD11c-restricted Wnt4 deficiency increased IL-5 production, group 2 innate lymphoid cell expansion, and host resistance to the hookworm parasite Nippostrongylus brasiliensis. Collectively, these data uncover a novel and unexpected role for Wnt4 in cDC subset differentiation and type 2 immunity.

Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

“…The high expression of Wnt4 in lamina propria macrophages was recently confirmed by immunohistochemistry (IHC). Conditional deletion of Wnt4 using Itgax -cre led to dysregulation of immunity against an intestinal parasite [ 121 ]. WNT4 is a candidate mediator of the key trophic role of lamina propria macrophages in the intestinal stem cell niche [ 122 ].…”

“…Despite evidence that it is expressed by many resident tissue macrophages (reviewed in [ 25 ]), CD11C (encoded by Itgax ) is still widely used as a surface marker in mouse DC purification. Ongoing studies of the impacts of conditional mutations using Itgax -cre continue to be interpreted solely in terms of DC specificity (for example, [ 121 , 129 , 130 ]). Consistent with the literature [ 25 ], Itgax was expressed in multiple macrophage populations other than DCs ( Fig 2A ) at levels at least as high as in DCs purified using CD11C as a marker and correlated only with Cd22 , Cd274 (encoding programmed cell death 1 ligand 1), Csf2rb , Csf2rb2 , solute carrier ( Slc ) 15a3 , Tmem132a , and the transcription factor gene Prdm1 (Cluster145).…”

Differential regulation of the immune system in a brain-liver-fats organ network during short-term fasting

“…Nlrc3 , an NLR decoy/attenuator shown to attenuate inflammation in myeloid cells, showed increased expression (2.3 log 2 FC). Wnt4 has been shown to suppress dendritic cell responsiveness [ 56 ] and displayed increased expression levels by 3.3 Log 2 FC. Overall, in iBAT, the effector T cell and innate signaling were reduced, suggesting an anti-inflammatory state during STF.…”

Differential regulation of the immune system in a brain-liver-fats organ network during short term fasting

“…The components of the Nod-like receptor pathway, Nod2, and Aim2 were also expressed at lower levels (-1.6 and -4.4 log2FC, respectively), while Nlrc3, an NLR decoy/attenuator shown to attenuate inflammation in myeloid cells, showed increase expression (2.3 log2FC). Wnt4 has been shown to suppress dendritic cell responsiveness [43] and was increased by 3.3 log2FC. Overall, in iBAT, the effector T cell and innate signaling were reduced, suggesting an anti-inflammatory state during STF.…”