The role of monocytes in IFN-based SLE signaling pathway

Secretory Carrier-Associated Membrane Protein 5 encoding gene (SCAMP5) is a candidate risk gene for Systemische Lupus Erythematodes (SLE) and lupus that selectively expressed by plasmacytoid dendritic cells (pDCs) among the leukocytes in peripheral blood at both transcript and protein level. SCAMP5 is localized in interferon (IFNs) secretory pathway in live cells, normally IFNs are produced by infected cells, pDCs, conventional dendritic cells (cDCs) and monocytes, among them pDCs are the principle producer of type 1 IFNs in SLE. From the previous work, SCAMP5 is colocalised with IFNα in activated pDCs. While the downstream effects of type1 IFNs on monocytes still remain to be studied.

Peptide-containing cytokine (CCL5 /RANTES) is associated with disease activity of SLE and lupus, with an elevated level in SLE patients compare with health controls. The cytokine interleukin-1β (IL-1β) is regarded as the key mediator of the inflammatory response. Interestingly, hSCAMP5 can promote the calcium-regulated signal CCL5 secretion in human monocytes but not IL-1β. Therefore, the mechanisms behind target to how monocytes contribute to SLE come to notice.

We wonder how monocytes integrate an IFN-based SLE signaling signature, as bridging cells between pDCs and adaptive immune pathology. Specifically, the research objectives will involve 1. investigate the relation between hyper-release of CCL5/RANTES in monocytes and type1 IFN release by pDCs in SLE, by measuring CCL5/RANTES with exposure to IFNa/b; 2. whether innate activation of monocytes contribute to CCL5/RANTES release and IL-1β release; 3. whether SCAMP5 contributes CCL5/RANTES release on monocytes, 4. detect the pre-activation status of monocytes from SLE patients, by focusing on SCAMP5 colocalization with CCL5/RANTES; 5. measure CCL5/RANTES in urine from SLE patients and health donors, and so on.

The outcomes from this project may support to find a newly therapeutic target for SLE and lupus by reducing CCL5/RANTES release.

Xiaolin Cao