Lipopolysaccharide-mediated macrophage polarization, conserved pathogenesis, and implications for peripheral neuropathy: a systematic review

OBJECTIVE AND DESIGN: This systematic review synthesized evidence for a conserved lipopolysaccharide (LPS)-mediated pathogenic mechanism across diverse tissues and evaluated its potential relevance to peripheral neuropathy.

METHODS: Studies were identified in which LPS was the independent exposure and pro-inflammatory, M1-like macrophage activation/polarization was an outcome. Structured evidence mapping was used to code in-vivo studies for direct measurement of prespecified steps along a proposed pathway: gut perturbation→barrier disruption→circulating LPS→systemic inflammation→tissue interface disruption→innate immune activation→M1-like macrophage skew→tissue dysfunction. Conditional concordance and downstream chain completeness scores were calculated.

RESULTS: Mechanistic patterns were conserved between pulmonary, cardiac, renal, lymphatic, gastrointestinal, central nervous, adipose, osseous, urologic, dental, hepatic, uterine, and pancreatic tissues. Conditional concordance with the proposed pathway was high (mean 0.984 ± 0.053). Eleven studies assessed all downstream steps from LPS exposure to tissue dysfunction, each demonstrating full chain completeness. M1 macrophage skew (87%), innate immune activation (87%), and circulating LPS (82.6%) were the most frequently reported steps.

CONCLUSIONS: These findings demonstrate conservation of LPS-driven M1-like macrophage polarization and tissue injury across systems, supporting the need to further investigate the biological plausibility of a gut-immune-nerve axis contributing to peripheral neuropathy.