Diabetes-induced hyperglycemia increases the extracellular concentration of methylglyoxal. Methylglyoxal-derived hydroimidazolones (MG-H) form advanced glycation end products (AGEs) that accumulate in the serum of diabetic patients. The binding of hydroimidozolones to the receptor for AGEs (RAGE) results in long-term complications of diabetes typified by vascular and neuronal injury. Here we show that binding of methylglyoxal-modified albumin to RAGE results in signal transduction. Chemically synthesized peptides containing hydroimidozolones bind specifically to the V domain of RAGE with nanomolar affinity. The solution structure of an MG-H1–V domain complex revealed that the hydroimidazolone moiety forms multiple contacts with a positively charged surface on the V domain. The high affinity and specificity of hydroimidozolones binding to the V domain of RAGE suggest that they are the primary AGE structures that give rise to AGEs–RAGE pathologies.

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Monocytes and macrophages represent critical arms of the innate immune system and are considered regulators and effectors of inflammation and the innate immune response. Monocytes can mobilize from bone marrow, traffic to their required destination, and differentiate into effector cells, depending on the local tissue environment, to perform multiple roles during infection or inflammation, making them important components of body's immune defense. Macrophages have diverse roles in tissue homeostasis, development, and tissue repair following injury. Adult bone marrow monocytes can give rise to tissue-resident macrophages during infection or inflammatory reactions, besides self-replication of tissue resident macrophages. Lysophosphatidic acid (LPA), a lipid by-product of autotaxin activity, is involved in cancer, vascular defects, and neural tissue, but is largely unexplored in immune system. Here, we reveal an unexpected function of LPA that transfigures CD11b murine monocytes into F4/80 macrophages. LPA-stimulated Akt/mTOR signaling is critical for LPA-mediated macrophage development in mice. Additionally, transcriptome analysis reveals that PPARγ is the key transcriptional regulator in the development of LPA-induced macrophages. In humans, LPA mediates macrophage formation following similar pathways. These findings identify a critical role for LPA in regulating innate immune system.