Macrophage β2-AR activation amplifies inflammation in wound healing by upregulating Trem1 via the cAMP/PKA/CREB pathway

Inflammation is an important part of the wound healing process. The stress hormone epinephrine has been demonstrated to modulate the inflammatory response via its interaction with β2-adrenergic receptor (β2-AR). However, the precise molecular mechanism through which β2-AR exerts its influence on inflammation during the wound healing process remains an unresolved question. Transcriptome datasets of wound and macrophages from the GEO database were reanalyzed using bioinformatics. The role of β2-AR in wound healing was explored by a mouse hind paw plantar wound model, and histological analyses were performed to assess wound healing. In vivo and in vitro assays were performed to elucidate the role of β2-AR on the inflammatory response. Triggering receptor expressed on myeloid cells 1 (Trem1) was knocked down with siRNA on RAW cells and western blot and qPCR assays were performed. Trem1 was upregulated within 24 h of wounding, and macrophage β2-AR activation also upregulated Trem1. In vivo experiments demonstrated that β2-AR agonists impaired wound healing, accompanied by upregulation of Trem1 and activation of cAMP/PKA/CREB pathway, as well as by a high level of pro-inflammatory cytokine production. In vitro experiments showed that macrophage β2-AR activation amplified LPS-induced inflammation, and knockdown of Trem1 reversed this effect. Using activator and inhibitor of cAMP, macrophage β2-AR activation was confirmed to upregulate Trem1 via the cAMP/PKA/CREB pathway. Our study found that β2-AR agonists increase Trem1 expression in wounds, accompanied by amplification of the inflammatory response, impairing wound healing. β2-AR activation in RAW cells induces Trem1 upregulation via the cAMP/PKA/CREB pathway and amplifies LPS-induced inflammatory responses.