In another study, a discrete subset of myeloid (CD11b+) DCs was t

In another study, a discrete subset of myeloid (CD11b+) DCs was the only cell type in spleen that transcribed IFN-β1 genes after systemic DNP Cell Cycle inhibitor treatment, though other cell types ingested DNPs and contained cargo DNA [33]. Thus it may not be a coincidence

that, in a recent study to examine antigen uptake in living lymphoid tissues using intra-vital techniques, CD11b+ DCs were shown to ingest particulate antigens rapidly [35]. Other spleen cells have also been shown to ingest DNPs rapidly. Marginal zone macrophages (MZMs; CD169+, F4/80neg) in mouse spleen ingested DNPs rapidly and avidly, but unlike CD11b+ DCs, no DNP cargo DNA was detected in MZMs [33], suggesting that MZMs ingest and degrade particulate material containing DNA such as chromatin, which resembles DNPs before DNA accesses the cytosol; this scenario is consistent with the ability of MZMs to remove blood-borne particulate

materials Doxorubicin order in a way that does not incite autoimmunity [36]. Unlike MZMs, some splenic CD8α+ DCs and myeloid non-DCs (CD11b+CD11cneg) also ingested DNPs and retained cargo DNA but did not transcribe IFN-β1 genes [33], suggesting that cytosolic DNA sensing to activate the STING/IFN-β pathway may be defective in these cell types. Treating mice with cdiGMP elicited responses in the spleen that were remarkably similar to those induced by DNPs [33], reinforcing the conclusions that myeloid DCs are “first-responder cells” and are specialized to sense cytosolic DNA and CDNs, and that the DNA sensing STING/IFN-β pathway may be functionally defective in other “nonresponder” cells. DNP and cdiGMP treatments were also shown to induce comparable patterns of IL-1β transcription via a STING-independent pathway [33]; however, myeloid non-DCs (not myeloid DCs)

expressed the highest levels of IL-1β transcripts. Another recent report revealed that bacterial CDNs stimulate mucosal immunity in mice via a pathway dependent on STING and NFκB signaling but not IRF3 and IFN-αβ signaling to induce TNF-α [37]. In summary, responses to DNA by innate immune cells are surprisingly complex and functionally PARP inhibitor dichotomous, revealing tissue-, cell-type-, and pathway-specific differences in how innate immune cells respond to DNA. The molecular basis of such complex physiologic responses to DNA are poorly understood but are critically important for elucidating pivotal pathways that control downstream immune responses to DNA. Cytosolic DNA sensing to induce regulation via STING may be biologically significant for several reasons. Regulatory responses to DNA may help maintain self-tolerance during homeostasis and inflammation, thereby reducing the risk of inciting autoimmunity.

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