Autophagy is a cellular process for the lysosomal degradation and recycling of cytosolic constituents, including dysfunctional or damaged organelles, long-lived macromolecules and intracellular pathogens. Autophagy has multiple roles to play in immune cell homeostasis, impacting both innate and adaptive immune responses. Moreover, dysfunctional autophagy has been associated with pathology in several inflammatory and autoimmune diseases, including inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus (SLE). Previous studies have shown that autophagy regulates the release of multiple cytokines from different immune cells, including negative regulation of pro-inflammatory mebers of theinterleukin-1 family of cytokines. Here, we looked at cytokine release in mouse models of SLE and LPS-induced endotoxemia using mice with a myeloid cell specific deletion in the autophagy gene Atg7 (Atg7fl/flLysMCre). We found that loss of Atg7 in myeloid cells resulted in reduced production of specific autoantibodies and lower levels of serum IL-6 and IL-10. In contrast, in response to intraperitoneal injection of LPS, Atg7fl/flLysMCre mice produced significantly higher levels of IL-1α, IL-1β, IL-6 and IL-12 in the peritoneal cavity than WT mice and higher levels of IL-1α, IL-1β, IL-18, IL-17A and IFNγ systemically. In vitro, manipulation of autophagy had inconsistent effects on Toll-like receptor (TLR)-dependent IL-6 release by macrophages. However, in human and mouse myeloid cells, loss of autophagy consistently resulted in decreased TLR-dependent IL-10 release, while induction of autophagy with the mTOR inhibitor Torin 1 increased IL-10 release. Our data suggest that myeloid cell autophagy has different effects on cytokine release in chronic vs acute inflammation, regulates multiple cytokines and has direct effects on IL-10 release by macrophages in vitro and in vivo. This highlights potentially critical differences in the role of myeloid cell autophagy in acute and chronic inflammation and demonstrates a direct role for autophagy in the release of IL-10 by macrophages.