Soluble CD14 through GABA production by monocytes promotes Th17 differentiation and innate lymphoid cells 3740

Abstract Description Soluble CD14 (sCD14) plays a pivotal role in immunity, with elevated levels linked to numerous acute and chronic conditions, including COVID-19, HIV, and cardiovascular diseases. Studies highlight monocytes as the primary source of sCD14, particularly under endotoxin or LPS stimulation. sCD14 enhances inflammatory responses, amplifying macrophage and neutrophil activation, yet can suppress LPS-stimulated monocyte responses in whole blood. It also modulates B cell activity, increasing IgG1 and IL-6 production, while inhibiting T cell proliferation and cytokine release (e.g., IL-2, IFN-γ, TNF-a). Our studies reveal that sCD14 indirectly promotes Th17 differentiation by reducing Th1 responses and upregulating Th17-related cytokines (e.g., IL-17A, IL-17F). This mechanism expands Th17 cells and polarizes naïve CD4+ and CD8+ T cells toward Th17 phenotypes, implicated in inflammatory diseases like psoriasis and multiple sclerosis. Additionally, sCD14-treated T cells secrete unique chemokines, including IP-10 and TARC, enhancing inflammation. We found that sCD14 through GABA production by monocytes promote IL-17 and innate lymphoid cells (ILCs), which express Th17-associated markers. GABA further drives Th17 differentiation through mTOR signaling. These findings underscore sCD14’s multifaceted role in shaping immune responses, especially in promoting Th17-mediated inflammation and related pathologies. Funding Sources This study was supported by a CIHR grant to SE and a CIHR-REDI award to S.S. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)