Bellassen L., David K., Lampert B., Sarusi-Portuguez A., Tsoory M., Lubliner J., Hornstein E., Osherov M., Milo R., Brenner O., Becker-Herman S. & Shachar I.
(2025)
PLoS Biology.
23,
9 September,
e3003373.
Multiple sclerosis (MS) is a chronic neurological disorder characterized by demyelination of the central nervous system (CNS), leading to a broad spectrum of physical and cognitive impairments. Myeloid cells within the CNS, including microglia and border-associated macrophages, play a central role in the neuroinflammatory processes associated with MS. Activation of these cells contributes to the local inflammatory response and promotes the recruitment of additional immune cells into the CNS. SLAMF5 is a cell surface receptor that functions as a homophilic adhesion molecule, capable of modulating immune cell activity through both activating and inhibitory signals. In this study, we investigated the expression and function of SLAMF5 in CNS-resident and peripheral myeloid cells using the murine model of MS experimental autoimmune encephalomyelitis (EAE). Our findings demonstrate that both total and brain-specific SLAMF5 deficiency in myeloid cells leads to decreased expression of activation and costimulatory molecules, including MHC class II (MHCII) and CD80. This downregulation is mediated, at least in part, through the transcription factor BHLHE40 and its regulation of CD52, resulting in delayed onset and reduced progression of the disease. Furthermore, pharmacological blockade of SLAMF5 in the brain halted disease progression and reduced the expression of myeloid activation markers. In human studies, SLAMF5 blockade in peripheral monocytes from MS patients and in induced pluripotent stem cell (iPSC)-derived microglia reduced the expression of HLA-DR, CD80, and CD52. Together, these results identify SLAMF5 as a key regulator of myeloid cell activation in neuroinflammation and suggest that it may represent a promising therapeutic target for autoimmune disorders such as MS.
Rabani S., Gunes E. G., Gunes M., Pellegrino B., Lampert B., David K., Pillai R., Li A., Becker-Herman S., Rosen S. T. & Shachar I.
(2024)
Cell Reports.
43,
11,
114920.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. The tumor microenvironment (TME) plays a major regulatory role in TNBC progression and is highly infiltrated by suppressive immune cells that reduce anti-tumor immune activity. Although regulatory B cells (Bregs) are a key TME component, knowledge of their function in TNBC is limited. CD84 is a homophilic adhesion molecule that promotes the survival of blood tumors. In the current study, we followed the role of CD84 in the regulation of the TME in TNBC. We demonstrate that CD84 induces a cascade in Bregs that involves the β-catenin and Tcf4 pathway, which induces the transcription of interleukin-10 by binding to its promoter and the promoter of its regulator, AhR. This leads to the expansion of Bregs, which in turn control the activity of other immune cells and immune suppression. Accordingly, we suggest CD84 as a therapeutic target for breaking immune tolerance in TNBC.
Lewinsky H., Gunes E. G., David K., Radomir L., Kramer M. P., Pellegrino B., Perpinial M., Chen J., He T. F., Mansour A. G., Teng K. Y., Bhattacharya S., Caserta E., Troadec E., Lee P., Feng M., Keats J., Krishnan A., Rosenzweig M., Yu J., Caligiuri M. A., Cohen Y., Shevetz O., Becker-Herman S., Pichiorri F., Rosen S. & Shachar I.
(2023)
Africa Insight.
8,
14,
The authors recently became aware of inadvertent errors in Figure 1F. In the original version, the representative flow plots provided for CD14 HD-PD and CD14+ HD-PD were incorrect.
