A study led by Professor Li Wu at the Institute of Immunology, Tsinghua University, was published in Volume 2 of the journal Immunity & Inflammation on October 19, 2026. The article reports that HDAC1 and HDAC2 are key epigenetic regulators of alveolar macrophages (AMs), jointly promoting their differentiation and survival. Combined deletion of HDAC1 and HDAC2 leads to severe AM loss, alveolar proteinosis-like pathological changes, and significantly increased susceptibility to influenza virus infection in mice.
AMs are among the most important tissue-resident macrophages in the lung. They serve as the first line of immune defense against respiratory pathogens and are essential for maintaining the metabolism of pulmonary surfactant and lung homeostasis. Multiple cytokines and transcription factors have been identified as regulators of AM development and differentiation; however, the role of epigenetic regulation in maintaining AM homeostasis has remained to be further clarified.
HDAC1 and HDAC2 belong to class I histone deacetylases. They share high sequence similarity and exhibit functional redundancy in many cell types. In this study, the researchers found that combined deletion of Hdac1 and Hdac2 led to near-complete loss of AMs, whereas deletion of Hdac1 or Hdac2 alone had no obvious effect on AM numbers. Using different Cre-driven conditional gene knockout systems and competitive bone marrow chimeric experiments, the team confirmed that HDAC1 and HDAC2 exert important cell-intrinsic regulatory effects on AM maintenance.
The study further showed that HDAC1/2 deficiency produces pathological consequences beyond macrophage loss. AMs not only maintain the alveolar environment but also form an important component of respiratory innate immune defense. Mice with combined HDAC1/2 deficiency displayed obvious alveolar proteinosis-like features, including significantly elevated total protein levels in bronchoalveolar lavage fluid and accumulation of surfactant proteins in lung tissue. At the same time, compared with control mice, HDAC1/2-deficient mice showed significantly increased susceptibility to influenza virus infection, with more severe body weight loss and lung tissue damage, impaired pulmonary viral clearance, higher viral titers, and significantly increased mortality. These findings indicate that AM homeostasis mediated by HDAC1 and HDAC2 plays an important role in pulmonary surfactant clearance and antiviral defense.
Mechanistically, the researchers found that HDAC1/2 maintain AM homeostasis through two aspects. On the one hand, HDAC1/2 promote AM survival by inhibiting the pro-apoptotic protein Bim expression. In HDAC1/2-deficient AMs, Bim was markedly elevated, whereas anti-apoptotic proteins such as Bcl-2 showed no obvious change. The HDAC deacetylase inhibitor FK228 similarly induced increased Bim expression in AMs and promoted AM apoptosis; knockdown of Bim partially improved AM survival under this condition.
On the other hand, HDAC1/2 interact with LSD1 to regulate AM differentiation. The study showed that Bim knockdown alone did not significantly restore the ability of HDAC1/2-deficient hematopoietic precursor cells to differentiate into AMs, indicating that HDAC1/2 have additional regulatory mechanisms. Further investigation found that HDAC1 and HDAC2 have clear protein–protein interactions with the histone demethylase LSD1 (KDM1A), and that inhibition of LSD1 enzymatic activity with a small-molecule inhibitor or knockdown of Lsd1 with shRNA improved the differentiation defect of AMs under HDAC1/2 deficiency. Meanwhile, LSD1 inhibition did not significantly affect apoptosis or Bim expression, suggesting that LSD1 mainly participates in AM differentiation regulation rather than directly mediating the survival mechanism described above.
"This study reveals for the first time that HDAC1 and HDAC2 maintain AM homeostasis through regulation of Bim-mediated cell survival and an LSD1-involved AM differentiation program," the authors concluded. HDAC1/2 deficiency leads to reduced AMs, alveolar proteinosis-like pathology, and impaired antiviral defense in mice. "These findings provide a new theoretical basis for the epigenetic regulation of AMs and offer new perspectives for understanding tissue-resident macrophage homeostasis imbalance and related lung diseases," the authors highlighted.
