This study investigates the role of miR-146a in the immune system using genetically engineered mice. The researchers found that miR-146a is highly expressed in immune tissues and is upregulated in response to immune cell maturation and activation. Targeted deletion of the *miR-146a* gene in mice results in several immune-related phenotypes, including hyperresponsiveness to bacterial LPS, exaggerated inflammatory responses, and spontaneous autoimmune disorders characterized by splenomegaly, lymphadenopathy, and multiorgan inflammation. Mechanistically, miR-146a targets TRAF6 and IRAK1, which are crucial for pro-inflammatory signaling. Overexpression of miR-146a in monocytes dampens the inflammatory response, while its deficiency leads to excessive myeloid cell proliferation and tumor development in aging mice. These findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.This study investigates the role of miR-146a in the immune system using genetically engineered mice. The researchers found that miR-146a is highly expressed in immune tissues and is upregulated in response to immune cell maturation and activation. Targeted deletion of the *miR-146a* gene in mice results in several immune-related phenotypes, including hyperresponsiveness to bacterial LPS, exaggerated inflammatory responses, and spontaneous autoimmune disorders characterized by splenomegaly, lymphadenopathy, and multiorgan inflammation. Mechanistically, miR-146a targets TRAF6 and IRAK1, which are crucial for pro-inflammatory signaling. Overexpression of miR-146a in monocytes dampens the inflammatory response, while its deficiency leads to excessive myeloid cell proliferation and tumor development in aging mice. These findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.