Acute respiratory distress syndrome (ARDS) is a kind of comprehensive disease with excessive inflammation and high clinical mortality. Multiple immune cells are involved in the ARDS process. Amongst these populations, lung-resident alveolar macrophages (AMs) are known to participate in the regulation of ARDS. GPR84, a metabolite-sensing GPCR sensing medium-chain fatty acids (MCFAs), is highly expressed in LPS-challenged macrophages and considered as a pro-inflammatory receptor. In this study, it was hypothesized that Gpr84 may be involved in pulmonary homeostasis via its regulatory effect on the switch of AM status. In LPS-induced ALI mouse model, we identified the internal LPS-induced switch of AMs from CD11blo to more inflamed CD11bhi status, which is deeply related to the exacerbated imbalance of homeostasis in the lung injury process. Gpr84 was highly expressed in ALI lung tissues and involved in cytokine release, phagocytosis and status switch of AMs through positive regulatory crosstalk with TLR4-related pathways via CD14 and LBP, which relied on Akt, Erk1/2, and STAT3. If conserved in humans, GPR84 may represent a potential therapeutic target for ARDS.