Macrophage-Assisted DNA damage response

The DNA-damage response (DDR) is a comprehensive and complex network of phosphorylation-mediated signaling pathways that endogenously originates from the DNA lesion. Depending on the extent of DNA damage, the response leads to alternative cellular outcomes, ranging from DNA repair and normal replication, or in the face of incomplete repair to cell cycle arrest, senescence or apoptosis.

We recently provided evidence for a macrophage-dependent mechanism that regulates the response to DNA damage and cell fate decision. In this study we demonstrated that macrophages through the proteolytic release of macrophage-derived HB-EGF, enhance DDR in neighboring cells suffering from DNA damage. Consequently, HB-EGF-treated cells exhibit higher double-strand break (DSB) rejoining and display lower levels of residual DSBs. In vivo, macrophagedepletion or blocking HB-EGF activity in diethylnitrosamine (DEN)-treated mouse livers resulted in higher levels of non-repairable DSBs.

This study establishes for the first time that macrophages, acting through the activation of the EGF:EGFR cascade, constitutes an important and novel extrinsic, cell-non-autonomous component of the DDR. Hence, in addition to the autonomous mechanism of DNA damage response and repair that transpires inside the cell, there are cell-extrinsic or cell non-autonomous systemic mechanisms influencing the response to DNA damage. Such systemic regulation of the DNA damage response, which impacts a wide range of cells, is likely to contribute to a range of diseases and physiological events, such as cancer and aging.

Indeed, we further demonstrated that while HB-EGF enhanced DNA double strand break repair, chronic age-dependent secretion of pro-inflammatory cytokines (specifically TNFaand IL-1b), induced by gut microbiota, impaired the beneficial effect of EGFR signaling on DDR. Consequently, this process accounts for age-dependent decline in DNA damage repair capacity.