Figure 6 |. CHIP-mutant cells promote inflammation via both cell-intrinsic and paracrine effects.

a | In wild-type macrophages, TET2 facilitates the recruitment of histone deacetylase (HDAC) to the IL-6 promoter, thereby suppressing Il6 transcription through histone deacetylation¹³⁸. A similar mechanism operates at the IL-1β promoter, where TET2 downregulates Il1b transcription⁹. Additionally, TET2 limits the expression and activity of the NLRP3 inflammasome, reducing the release of mature IL-1β by activated macrophages. Contrastingly, TET2-deficient macrophages or those harboring TET2 loss-of-function mutations lack these regulatory mechanisms and thus IL-6 and IL-1β are overproduced in response to infection or inflammation, exacerbating inflammatory conditions such as atherosclerosis⁹. Ac denotes acetylated histone. b | Activated CHIP-mutant cells release cytokines and/or chemokines that can activate gene transcription in non-mutant cells within proximity. c | Activated CHIP-mutant macrophages secrete the indicated Th17-inducing cytokines resulting in enhanced release of IL-17 from WT Th17 cells. IL-17 in turn activates downstream targets, such as WT fibroblasts¹⁴⁰. d | Paracrine activation of WT platelets by TXA2-secreting Jak2^V617F platelets resulting in increased arterial thrombosis¹³¹. LPS, lipopolysaccharide; RANK, receptor activator of nuclear factor-κB ligand; RANKL, RANK ligand, TXA2, thromboxane A2.