Context-dependent lysophosphatidic acid signalling in inflammation: evidence hierarchy, myeloid regulation and translational gaps.

backgroundLysophosphatidic acid (LPA) has been extensively reviewed in receptor pharmacology, fibrosis, cancer, vascular biology and neural injury. Its role in inflammation remains difficult to interpret because well-replicated pathogenic or pro-remodelling actions coexist with selected macrophage-regulatory effects reported under defined experimental conditions.

findingsThis structured narrative review provides an evidence-weighted framework for interpreting these divergent findings. The strongest evidence supports LPA as an injury- and remodelling-associated signal in vascular-stromal programmes, pain-associated settings and tumour immune escape. By contrast, LPA-mediated attenuation of selected LPS/TLR4-driven macrophage responses is biologically plausible but incompletely replicated and receptor-divergent. The more specific LPAR1-dependent model of M2-like and metabolic macrophage reprogramming remains less independently validated, especially in primary human myeloid cells and physiologically plausible concentration ranges.

conclusionsLPA should not be classified as simply pro-inflammatory or anti-inflammatory. Anti-inflammatory LPA models should be regarded as experimentally plausible but translationally unproven until validated using defined LPA species, receptor-resolved perturbation and concentration-resolved human myeloid-cell systems.